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Nandakumar, Kutty SelvaORCID iD iconorcid.org/0000-0001-7790-8197
Publications (10 of 190) Show all publications
Gu, P., Liu, R., Yang, Q., Xie, L., Wei, R., Li, J., . . . Chen, P. (2023). A metabolite from commensal Candida albicans enhances the bactericidal activity of macrophages and protects against sepsis. Cellular & Molecular Immunology, 20(10), 1156-1170
Open this publication in new window or tab >>A metabolite from commensal Candida albicans enhances the bactericidal activity of macrophages and protects against sepsis
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2023 (English)In: Cellular & Molecular Immunology, ISSN 1672-7681, E-ISSN 2042-0226, Vol. 20, no 10, p. 1156-1170Article in journal (Refereed) Published
Abstract [en]

The gut microbiome is recognized as a key modulator of sepsis development. However, the contribution of the gut mycobiome to sepsis development is still not fully understood. Here, we demonstrated that the level of Candida albicans was markedly decreased in patients with bacterial sepsis, and the supernatant of Candida albicans culture significantly decreased the bacterial load and improved sepsis symptoms in both cecum ligation and puncture (CLP)-challenged mice and Escherichia coli-challenged pigs. Integrative metabolomics and the genetic engineering of fungi revealed that Candida albicans-derived phenylpyruvate (PPA) enhanced the bactericidal activity of macrophages and reduced organ damage during sepsis. Mechanistically, PPA directly binds to sirtuin 2 (SIRT2) and increases reactive oxygen species (ROS) production for eventual bacterial clearance. Importantly, PPA enhanced the bacterial clearance capacity of macrophages in sepsis patients and was inversely correlated with the severity of sepsis in patients. Our findings highlight the crucial contribution of commensal fungi to bacterial disease modulation and expand our understanding of the host-mycobiome interaction during sepsis development. © 2023, The Author(s), under exclusive licence to CSI and USTC.

Place, publisher, year, edition, pages
London: Nature Publishing Group, 2023
Keywords
Bacterial clearance, Candida albicans, Macrophage, Phenylpyruvate, Sepsis
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:hh:diva-51592 (URN)10.1038/s41423-023-01070-5 (DOI)001044726900001 ()2-s2.0-85167341099 (Scopus ID)
Note

Funding: The National Natural Science Foundation of China (32271230 and 32071124) to PC; the NIH Grant (P30DK120515) to BS; the National Natural Science Foundation of China (82270581) to YC; the National Key R&D Project of China (2018YFC0115301), the National Natural Science Foundation of China (81974070), the Shenzhen Science and Technology Program (JCYJ20210324131010027) and the Research Foundation of Shenzhen Hospital of Southern Medical University (PT2018GZR10) to WG.

Available from: 2023-09-07 Created: 2023-09-07 Last updated: 2024-01-16Bibliographically approved
Shakya, A. K., Mallick, B. & Nandakumar, K. S. (2023). A Perspective on Oral Immunotherapeutic Tools and Strategies for Autoimmune Disorders. Vaccines, 11(6), Article ID 1031.
Open this publication in new window or tab >>A Perspective on Oral Immunotherapeutic Tools and Strategies for Autoimmune Disorders
2023 (English)In: Vaccines, E-ISSN 2076-393X, Vol. 11, no 6, article id 1031Article, review/survey (Refereed) Published
Abstract [en]

Oral immune tolerance is a physiological process to achieve tolerance against autoimmunity by oral ingestion of self-antigen(s) or other therapeutics. At the cellular level, oral tolerance suppresses autoimmune diseases by activating FoxP-positive and -negative regulatory T cells (Tregs) and/or causing clonal anergy or deletion of autoreactive T cells, affecting B cell tolerance. However, oral delivery of antigens/biologics is challenging due to their instability in the harsh environment of the gastrointestinal (GI) tract. Several antigen/drug delivery tools and approaches, including micro/nanoparticles and transgenic plant-based delivery systems, have been explored to demonstrate oral immune tolerance for different autoimmune diseases successfully. However, despite the effectiveness, variation in results, dose optimization, and undesirable immune system activation are the limitations of the oral approach to further advancement. From this perspective, the current review discusses the oral tolerance phenomenon, cellular mechanisms, antigen delivery tools and strategies, and its challenges. © 2023 by the authors.

Place, publisher, year, edition, pages
Basel: MDPI, 2023
Keywords
antigen delivery system, autoimmune diseases, nanoparticles, oral route, rheumatoid arthritis, transgenic plants, type 1 diabetes
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:hh:diva-51435 (URN)10.3390/vaccines11061031 (DOI)001015857000001 ()37376420 (PubMedID)2-s2.0-85163580304 (Scopus ID)
Available from: 2023-08-17 Created: 2023-08-17 Last updated: 2023-08-17Bibliographically approved
Nandakumar, K. S., Fang, Q., Wingbro Ågren, I. & Bejmo, Z. F. (2023). Aberrant Activation of Immune and Non-Immune Cells Contributes to Joint Inflammation and Bone Degradation in Rheumatoid Arthritis. International Journal of Molecular Sciences, 24(21), Article ID 15883.
Open this publication in new window or tab >>Aberrant Activation of Immune and Non-Immune Cells Contributes to Joint Inflammation and Bone Degradation in Rheumatoid Arthritis
2023 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 24, no 21, article id 15883Article, review/survey (Refereed) Published
Abstract [en]

Abnormal activation of multiple immune and non-immune cells and proinflammatory factors mediate the development of joint inflammation in genetically susceptible individuals. Although specific environmental factors like smoking and infections are associated with disease pathogenesis, until now, we did not know the autoantigens and arthritogenic factors that trigger the initiation of the clinical disease. Autoantibodies recognizing specific post-translationally modified and unmodified antigens are generated and in circulation before the onset of the joint disease, and could serve as diagnostic and prognostic markers. The characteristic features of autoantibodies change regarding sub-class, affinity, glycosylation pattern, and epitope spreading before the disease onset. Some of these antibodies were proven to be pathogenic using animal and cell-culture models. However, not all of them can induce disease in animals. This review discusses the aberrant activation of major immune and non-immune cells contributing to joint inflammation. Recent studies explored the protective effects of extracellular vesicles from mesenchymal stem cells and bacteria on joints by targeting specific cells and pathways. Current therapeutics in clinics target cells and inflammatory pathways to attenuate joint inflammation and protect the cartilage and bones from degradation, but none cure the disease. Hence, more basic research is needed to investigate the triggers and mechanisms involved in initiating the disease and relapses to prevent chronic inflammation from damaging joint architecture. © 2023 by the authors.

Place, publisher, year, edition, pages
Basel: MDPI, 2023
Keywords
autoantibodies, B cells, fibroblasts, inflammation, macrophages, osteoclasts, rheumatoid arthritis, T cells
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:hh:diva-52112 (URN)10.3390/ijms242115883 (DOI)37958864 (PubMedID)2-s2.0-85176465928 (Scopus ID)
Available from: 2023-11-24 Created: 2023-11-24 Last updated: 2023-11-24Bibliographically approved
Wu, H., Ou, J., Li, K., Wang, T. & Nandakumar, K. S. (2023). Comparative Studies On Mannan and Imiquimod Induced Experimental Plaque Psoriasis Inflammation In Inbred Mice. Clinical and Experimental Immunology, 211(3), 288-300
Open this publication in new window or tab >>Comparative Studies On Mannan and Imiquimod Induced Experimental Plaque Psoriasis Inflammation In Inbred Mice
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2023 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 211, no 3, p. 288-300Article in journal (Refereed) Published
Abstract [en]

Psoriasis is a genetically determined, environmentally triggered, immune systemmediated autoimmune disease. Different animal models are needed to investigate the complex pathological mechanisms underlying this disease. Therefore, we established mannan induced psoriasis model and compared with the most commonly used imiquimod induced psoriasis in terms of disease, induction of innate immune cells, expression of cytokines and the effect of dexamethasone treatment. Mannan significantly induced more severe psoriasis with better disease relapsing feature than IMQ. As determined by immunohistochemistry, IMQ induced significantly more infiltration of CD11c+ and F4/80+ cells than mannan in the skin. However, cytometric analysis showed a significant increase in the percentage of Gr-1+ neutrophils in the spleen and lymph nodes as well as F4/80+ macrophages in the spleen after mannan exposure. Variation in the percentage of significantly increased Vγ4 T cells was also found to be dependent on the lymphoid organs tested. However, there is a clear difference between these models in terms of expression of certain cytokine genes: IL22, IL-23, IL-17E and IL-17F were expressed more predominantly in mannan induced inflammation, while IL-6 and IL-17A expressions were significantly higher in IMQ model. Interestingly, dexamethasone treatment strongly reduced epidermal thickness and histological scores induced by mannan than IMQ. Despite inducing psoriasis-like inflammation, certain differences and similarities were observed in the immune responses induced by mannan and IMQ. However, mannan induced psoriasis model is relatively more simple, economical and less harmful to mice with an increased possibility to develop a chronic psoriasis model by exposing mice to mannan.

Place, publisher, year, edition, pages
Oxford: Oxford University Press, 2023
Keywords
Psoriasis, Innate immune cells, γδ T cells, IL-23/IL-17 axis, Mannan, IMQ
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:hh:diva-48960 (URN)10.1093/cei/uxad004 (DOI)000935394800001 ()36645209 (PubMedID)2-s2.0-85151044499 (Scopus ID)
Available from: 2022-12-19 Created: 2022-12-19 Last updated: 2023-08-11Bibliographically approved
Wu, H. & Nandakumar, K. S. (2023). Epicutaneous Application of Mannan Induces Psoriasis-like Inflammation in an Inbred Mouse Strain. Bio-protocol, 13(20), Article ID e4845.
Open this publication in new window or tab >>Epicutaneous Application of Mannan Induces Psoriasis-like Inflammation in an Inbred Mouse Strain
2023 (English)In: Bio-protocol, E-ISSN 2331-8325, Vol. 13, no 20, article id e4845Article in journal (Refereed) Published
Abstract [en]

Mannan from yeast induces psoriasis-like inflammation in the skin of inbred mouse strains. Limitations of available models led us to develop a new psoriasis model with a rapid disease onset, severe disease course, short duration, and a simple and easy-to-induce protocol with much more practically convenient features and cost-benefits. Mannan-induced skin inflammation (MISI) is more severe than the classical imiquimod (IMQ)-induced skin inflammation (IISI), with characteristic features resembling human plaque psoriasis but with relatively fewer toxicity issues. Epicutaneous application of mannan (5 mg) in incomplete Freund’s adjuvant or Vaseline induces severe psoriasis in BALB/c female mice. Psoriasis area and severity index (PASI) and histological evaluation of the skin could help assess the disease development. MISI mimics natural environmental factors affecting the skin relatively more closely than IISI. This disease model can be used to dissect inflammatory pathways in the skin, identify genetic and environmental factors affecting psoriasis, and test potential pharmacological agents or new combinations of available drugs for treatment before designing clinical trials. © 2023 The Authors; exclusive licensee Bio-protocol LLC.

Place, publisher, year, edition, pages
Sunnyvale, CA: Bio-protocol LLC, 2023
Keywords
Imiquimod, Inflammation, Mannan, Mouse model, Psoriasis
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:hh:diva-52076 (URN)10.21769/BioProtoc.4845 (DOI)37900099 (PubMedID)2-s2.0-85175724655 (Scopus ID)
Note

Funding: Southern Medical University for high-level talent introduction project grants (C1051004, C1034211) given to KSN.

Available from: 2023-11-20 Created: 2023-11-20 Last updated: 2023-11-20Bibliographically approved
Li, Y., Li, Z., Nandakumar, K. S. & Holmdahl, R. (2023). Human NCF190H Variant Promotes IL-23/IL-17—Dependent Mannan-Induced Psoriasis and Psoriatic Arthritis. Antioxidants, 12(7), Article ID 1348.
Open this publication in new window or tab >>Human NCF190H Variant Promotes IL-23/IL-17—Dependent Mannan-Induced Psoriasis and Psoriatic Arthritis
2023 (English)In: Antioxidants, ISSN 2076-3921, Vol. 12, no 7, article id 1348Article in journal (Refereed) Published
Abstract [en]

Recently, a major single nucleotide variant on the NCF1 gene, leading to an amino acid replacement from arginine to histidine at position 90 (NCF1R90H), associated with low production of reactive oxygen species (ROS), was found to be causative for several autoimmune diseases. Psoriasis in the skin (PsO) and psoriatic arthritis (PsA) were induced with mannan by intraperitoneal injection or epicutaneous application, evaluated by visual and histology scoring. Immunostaining was used to identify macrophages, NCF1, and keratinocytes. The population of immune cells was quantified by flow cytometry, gene expression was analyzed by RT-qPCR, and the JAK/STAT signaling pathway was investigated by immunohistochemical staining and western blot. We found that the low ROS responder NCF190H variant promotes PsO and PsA (the MIP model). The NCF190H-expressing mice had hyperactivated macrophages, expanded keratinocytes, and dramatically increased numbers of γδT17 cells with upregulated IL-17A, IL-23, and TNF-α. In addition, the JAK1/STAT3 signaling pathway was also upregulated in cells in the psoriatic skin tissues of Ncf190H mice. To summarize, a defined SNP (NCF1-339, also named NCF190H) was found to activate the IL-23/IL-17 axis and JAK-STAT signaling pathways, leading to hyperactivation of macrophages and keratinocytes and causing mouse psoriasis and psoriatic arthritis. © 2023 by the authors.

Place, publisher, year, edition, pages
Basel: MDPI, 2023
Keywords
IL-23/IL-17 axis, JAK-STAT, macrophages, NCF1, psoriasis, ROS
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:hh:diva-51382 (URN)10.3390/antiox12071348 (DOI)001037963800001 ()37507888 (PubMedID)2-s2.0-85165938097 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2019-0059Swedish Research Council, 2019-01209
Note

Funding: This study was supported by an SMU grant (C1034211), the Natural Science Foundation of China (No. 32070913), the Knut and Alice Wallenberg Foundation (2019-0059), the Swedish Research Council (2019-01209), and the LEO foundation (LF-OC-22-001023).

Available from: 2023-08-14 Created: 2023-08-14 Last updated: 2023-08-14Bibliographically approved
Li, Y., Cui, H., Li, S., Li, X., Guo, H., Nandakumar, K. S. & Li, Z. (2023). Kaempferol modulates IFN-γ induced JAK-STAT signaling pathway and ameliorates imiquimod-induced psoriasis-like skin lesions. International Immunopharmacology, 114, Article ID 109585.
Open this publication in new window or tab >>Kaempferol modulates IFN-γ induced JAK-STAT signaling pathway and ameliorates imiquimod-induced psoriasis-like skin lesions
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2023 (English)In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 114, article id 109585Article in journal (Refereed) Published
Abstract [en]

Immune-mediated inflammation contributes to the development of psoriasis. However, long-term treatment with global immunosuppressive agents may cause a variety of side effects including recurrent infections. Kaempferol (KP), a natural flavonol, present in various plants is proposed to be useful for the treatment of psoriasis patients. Nevertheless, an explicit understanding of KP induced mechanisms is a prerequisite for its use in clinics. Therefore, we investigated the therapeutic effects and potential mode of action of KP using IFN-γ induced HaCaT cells and imiquimod-induced psoriasis-like skin lesions in mice. In this study, we found KP reduced intracellular ROS production, inhibited rhIFN-γ-induced IFN-γR1 expression, and up-regulated SOCS1 levels in HaCaT cells. In addition, KP inhibited rhIFN-γ-induced phosphorylation of JAK-STAT signaling molecules in HaCaT cells. Most importantly, KP alleviated imiquimod-induced psoriasis-like skin lesions in mice, histopathology and proportion of DCs in the skin. Besides, it reduced the population of γδT17 cells in the lymph nodes of the psoriatic mice and also decreased the gene expression of many proinflammatory cytokines, including interleukin IL-23, IL-17A, TNF-α, IL-6, and IL-1β in addition to down-regulation of the proinflammatory JAK-STAT signaling pathway. Thus, KP modulated IFN-γ induced JAK-STAT signaling pathway by inducing IFN-γR1 expression and up-regulating SOCS1 expression. In addition, KP also ameliorated imiquimod-induced psoriasis by reducing the dendritic cell numbers, and γδT17 cell population, along with down- modulation of the JAK-STAT pathway. © 2022 Elsevier B.V.

Place, publisher, year, edition, pages
London: Elsevier, 2023
Keywords
Kaempferol, Psoriasis, JAK-STAT, IFN-γR, SOCS1, γδT17 cell
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:hh:diva-48944 (URN)10.1016/j.intimp.2022.109585 (DOI)000906660700001 ()36527884 (PubMedID)2-s2.0-85144078305 (Scopus ID)
Note

Funding sponsor: Southern Medical University. Funding number: C1034211, C1051004.

Available from: 2022-12-16 Created: 2022-12-16 Last updated: 2023-08-21Bibliographically approved
Xu, M., Du, R., Xing, W., Chen, X., Wan, J., Xiong, L., . . . Geng, H. (2023). Platelets derived citrullinated proteins and microparticles are potential autoantibodies ACPA targets in RA patients. Frontiers in Immunology, 14, Article ID 1084283.
Open this publication in new window or tab >>Platelets derived citrullinated proteins and microparticles are potential autoantibodies ACPA targets in RA patients
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2023 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1084283Article in journal (Refereed) Published
Abstract [en]

Citrullinated neoepitopes have emerged as key triggers of autoantibodies anti-citrullinated protein antibodies (ACPA) synthesis in rheumatoid arthritis (RA) patients. Apart from their critical role in homeostasis and thrombosis, platelets have a significant contribution to inflammation as well. Although anuclear in nature, platelets have an intricate post-translational modification machinery. Till now, citrullination in platelets and its contribution to trigger autoantibodies ACPA production in RA is an unexplored research direction. Herein, we investigated the expression of peptidylarginine deiminase (PAD) enzymes and citrullinated proteins/peptides in the human platelets and platelet derived microparticles (PDP). Both PAD4 mRNA and protein, but not the other PAD isoforms, are detectable in the human platelets. With a strict filtering criterion,108 citrullination sites present on 76 proteins were identified in the human platelets, and 55 citrullinated modifications present on 37 different proteins were detected in the PDPs. Among them, some are well-known citrullinated autoantigens associated with RA. Citrullinated forms of thrombospondin-1, β-actin, and platelet factor-4 (also known as CXCL4) are highly immunogenic and bound by autoantibodies ACPA. Furthermore, ACPA from RA sera and synovial fluids recognized citrullinated proteins from platelets and significantly activated them as evidenced by P-selectin upregulation and sCD40 L secretion. These results clearly demonstrate the presence of citrullinated autoantigens in platelets and PDPs, thus could serve as potential targets of ACPA in RA. Copyright © 2023 Xu, Du, Xing, Chen, Wan, Wang, Xiong, Nandakumar, Holmdahl and Geng.

Place, publisher, year, edition, pages
Lausanne: Frontiers Media S.A., 2023
Keywords
rheumatoid arthritis, citrullination, platelets, anti-citrullinated protein antibodies (ACPA), platelet derived microparticles (PDP)
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:hh:diva-49835 (URN)10.3389/fimmu.2023.1084283 (DOI)000924887900001 ()36761728 (PubMedID)2-s2.0-85147442983 (Scopus ID)
Funder
Swedish Research Council, 2019-01209
Note

Funding: The Natural Science Foundation of China (32170906), Fundamental Research Funds for the Central University of Central China Normal University (CCNU20TS02112), and the Swedish Research Council (2019-01209).

Available from: 2023-01-18 Created: 2023-01-18 Last updated: 2024-01-17Bibliographically approved
Shakya, A. K. & Nandakumar, K. S. (2023). Polymer Chemistry Defines Adjuvant Properties and Determines the Immune Response against the Antigen or Vaccine. Vaccines, 11(9), Article ID 1395.
Open this publication in new window or tab >>Polymer Chemistry Defines Adjuvant Properties and Determines the Immune Response against the Antigen or Vaccine
2023 (English)In: Vaccines, E-ISSN 2076-393X, Vol. 11, no 9, article id 1395Article, review/survey (Refereed) Published
Abstract [en]

Activation of the immune system is a needed for designing new antigen/drug delivery systems to develop new therapeutics and for developing animal disease models to study the disease pathogenesis. A weak antigen alone is insufficient to activate the immune system. Sometimes, assistance in the form of polymers is needed to control the release of antigens under in vivo conditions or in the form of an adjuvant to activate the immune system efficiently. Many kinds of polymers from different functional groups are suitable as microbial antigens for inducing therapeutic immune responses against infectious diseases at the preclinical level. The choice of the functionality of polymer varies as per the application type. Polymers from the acid and ester groups are the most common types investigated for protein-based antigens. However, electrostatic interaction-displaying polymers like cationic polymers are the most common type for nucleic acid-based antigens. Metal coordination chemistry is commonly used in polymers designed for cancer immunotherapeutic applications to suppress inflammation and induce a protective immune response. Amide chemistry is widely deployed in polymers used to develop antigen-specific disease models like the experimental autoimmune arthritis murine model. © 2023 by the authors.

Place, publisher, year, edition, pages
Basel: MDPI, 2023
Keywords
antigen, autoimmunity, cancer, drug delivery, functional moiety, immune response, polymer, polymer chemistry
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:hh:diva-51779 (URN)10.3390/vaccines11091395 (DOI)001077857300001 ()37766073 (PubMedID)2-s2.0-85172220185 (Scopus ID)
Available from: 2023-11-17 Created: 2023-11-17 Last updated: 2023-11-17Bibliographically approved
Nandakumar, K. S. (2023). Vaccines and Vaccine Adjuvants for Infectious Diseases and Autoimmune Diseases. Vaccines, 11(2), Article ID 202.
Open this publication in new window or tab >>Vaccines and Vaccine Adjuvants for Infectious Diseases and Autoimmune Diseases
2023 (English)In: Vaccines, E-ISSN 2076-393X, Vol. 11, no 2, article id 202Article in journal, Editorial material (Refereed) Published
Place, publisher, year, edition, pages
Basel: MDPI, 2023
National Category
Microbiology in the medical area Immunology in the medical area
Identifiers
urn:nbn:se:hh:diva-49128 (URN)10.3390/vaccines11020202 (DOI)000942347800001 ()2-s2.0-85149125671 (Scopus ID)
Available from: 2023-01-06 Created: 2023-01-06 Last updated: 2023-08-11Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-7790-8197

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