{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T16:55:57Z","timestamp":1793120157634,"version":"4.5.0"},"reference-count":70,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"publisher","award":["ICMR- 61\/4\/2018-BMS"],"award-info":[{"award-number":["ICMR- 61\/4\/2018-BMS"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001501","name":"University Grants Commission","doi-asserted-by":"publisher","award":["UGC N045\/UGC-41\/2019\/RS"],"award-info":[{"award-number":["UGC N045\/UGC-41\/2019\/RS"]}],"id":[{"id":"10.13039\/501100001501","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Macrophages and natural killer (NK) cells are innate immune components proven to be either pathogenic, protective, or both in autoimmune disorders. Nonetheless, the function of macrophages in the pathogenesis of pemphigus vulgaris (PV), an autoimmune skin disorder, is lacking.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We aimed to investigate macrophages and their crosstalk with NK cells in PV, with a particular focus on how these interactions influence their functionalities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Flow cytometry and immunofluorescence was utilised to assess macrophage profile along with expression of receptors on NK cells and macrophages.\n                      <jats:italic>In-vitro<\/jats:italic>\n                      macrophage skewing, and NK\u2013macrophage interactions (including F-actin accumulation, activation markers, cytotoxicity, IFN\u03b3 and perforin secretion,\n                      <jats:italic>NOS2, CD86, CD206<\/jats:italic>\n                      expression, phagocytic activity, and arginase activity were examined. NKG2D blocking and related assays were performed to elucidate its role in crosstalk.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Expression of NKG2D on NK cells and MICA\/B on macrophages was upregulated. CD56\n                      <jats:sup>+<\/jats:sup>\n                      NK cells and CD68\n                      <jats:sup>+<\/jats:sup>\n                      macrophages co-localized in lesions. A significant increase in macrophages in both the periphery and lesional skin was observed. Both M1 and M2 macrophages were upregulated in blood, whereas M1 increased and M2 decreased in skin lesions. Macrophages displayed skewing toward an M2 phenotype\n                      <jats:italic>in vitro<\/jats:italic>\n                      . Upon co-culturing, F-actin accumulation increased during interaction. The interaction led to increased activation, cytotoxicity, and IFN\u03b3 and perforin secretion in NK cells when M1 stimulation and Dsg3 autoantigen were given. In macrophages, increased expression of iNOS and CD86 and higher phagocytic activity were noted, whereas arginase activity and expression along with CD206 were downregulated. NKG2D blockade on NK cells resulted in partial but significant decrease in NK cells activity including activation, perforin, cytotoxicity and IFN\u03b3 release. The reduction were prominent in M1 state. M1 like markers\n                      <jats:italic>NOS2<\/jats:italic>\n                      and\n                      <jats:italic>CD86<\/jats:italic>\n                      were reduced and arginase activity non significantly improved under M2 state post blockade.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study helped in comprehending functionally active NK- macrophage axis, where NK cells promote pro inflammatory M1 state, and dysregulate M2 macrophage functionality. NKG2D blockade resulted in partial reversal suggesting its critical, though not elusive, contribution indicating multifactorial crosstalk mechanism. Targeting NK cell activity or promoting M2 functionality could potentially lead to improvements in disease pathogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1774059","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T05:51:27Z","timestamp":1778219487000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["NK cell hyperactivation drives macrophage repolarization and limits M2 bias in pemphigus vulgaris"],"prefix":"10.3389","volume":"17","author":[{"given":"Vishakha","family":"Hooda","sequence":"first","affiliation":[{"name":"Department of Biochemistry, All India Institute of Medical Sciences","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aishwarya","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, All India Institute of Medical Sciences","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujay","family":"Khandpur","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Venereology, All India Institute of Medical Sciences","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudheer","family":"Arava","sequence":"additional","affiliation":[{"name":"Department of Pathology, All India Institute of Medical Sciences","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taruna","family":"Madan","sequence":"additional","affiliation":[{"name":"Division of Development Research, Indian Council of Medical Research","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alpana","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, All India Institute of Medical Sciences","place":["New Delhi, India"]},{"name":"Division of Development Research, Indian Council of Medical Research","place":["New Delhi, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.5826\/dpc.1202a116","article-title":"Serological biomarkers and their detection in autoimmune bullous skin diseases","volume":"12","author":"Heckler","year":"2022","journal-title":"Dermatol Pract Concept"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/ced.14041","article-title":"Pemphigus vulgaris and pemphigus foliaceus: an overview of the clinical presentation, investigations and management","volume":"44","author":"Melchionda","year":"2019","journal-title":"Clin Exp Dermatol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/6154397","article-title":"The significance of scalp involvement in pemphigus: a literature review","volume":"2018","author":"Sar-Pomian","year":"2018","journal-title":"BioMed Res Int"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1590\/abd1806-4841.20199011","article-title":"Pemphigus vulgaris*","volume":"94","author":"Porro","year":"2019","journal-title":"Anais Brasileiros Dermatologia"},{"key":"B5","unstructured":"Immunobullous Diseases - 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