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Intestinal inflammation alters the antigen-specific immune response to a skin commensal.

ABSTRACT: Resident microbes in skin and gut predominantly impact local immune cell function during homeostasis. However, colitis-associated neutrophilic skin disorders suggest possible breakdown of this compartmentalization with disease. Using a model wherein neonatal skin colonization by Staphylococcus epidermidis facilitates generation of commensal-specific tolerance and CD4⁺ regulatory T cells (Tregs), we ask whether this response is perturbed by gut inflammation. Chemically induced colitis is accompanied by intestinal expansion of S. epidermidis and reduces gut-draining lymph node (dLN) commensal-specific Tregs. It also results in reduced commensal-specific Tregs in skin and skin-dLNs and increased skin neutrophils. Increased CD4⁺ circulation between gut and skin dLN suggests that the altered cutaneous response is initiated in the colon, and resistance to colitis-induced effects in Cd4^creIl1r1^fl/fl mice implicate interleukin (IL)-1 in mediating the altered commensal-specific response. These findings provide mechanistic insight into observed connections between inflammatory skin and intestinal diseases.

SUBMITTER: Merana GR

PROVIDER: S-EPMC9248974 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Intestinal inflammation alters the antigen-specific immune response to a skin commensal.

Merana Geil R GR Dwyer Laura R LR Dhariwala Miqdad O MO Weckel Antonin A Gonzalez Jeanmarie R JR Okoro Joy N JN Cohen Jarish N JN Tamaki Courtney M CM Han Jungmin J Tasoff Preston P Palacios-Calderon Yasmin Y Ha Connie W Y CWY Lynch Susan V SV Segre Julia A JA Kong Heidi H HH Kattah Michael G MG Ma Averil A Scharschmidt Tiffany C TC

Cell reports 20220501 9

Resident microbes in skin and gut predominantly impact local immune cell function during homeostasis. However, colitis-associated neutrophilic skin disorders suggest possible breakdown of this compartmentalization with disease. Using a model wherein neonatal skin colonization by Staphylococcus epidermidis facilitates generation of commensal-specific tolerance and CD4<sup>+</sup> regulatory T cells (Tregs), we ask whether this response is perturbed by gut inflammation. Chemically induced colitis ...[more]

PMID: 35649365

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Project description:Surgical cytoreduction for patients with malignant pleural mesothelioma (MPM) is used for selected patients as a part of multi-modality management strategy. Our group has previously described the clinical use of photodynamic therapy (PDT), a form of non-ionizing radiation, as an intraoperative therapy option for MPM. Although necessary for the removal of bulk disease, the effects of surgery on residual MPM burden are not understood. In this bedside-to-bench study, Photofrin-based PDT introduced the possibility of achieving a long-term response in murine models of MPM tumors that were surgically debulked by 60% to 90%. Thus, the addition of PDT provided curative potential after an incomplete resection. Despite this success, we postulated that surgical induction of inflammation may mitigate the comprehensive response of residual disease to further therapy. Utilizing a previously validated tumor incision (TI) model, we demonstrated that the introduction of surgical incisions had no effect on acute cytotoxicity by PDT. However, we found that surgically induced inflammation limited the generation of antitumor immunity by PDT. Compared with PDT alone, when TI preceded PDT of mouse tumors, splenocytes and/or CD8+ T cells from the treated mice transferred less antitumor immunity to recipient animals. These results demonstrate that addition of PDT to surgical cytoreduction significantly improves long-term response compared with cytoreduction alone, but at the same time, the inflammation induced by surgery may limit the antitumor immunity generated by PDT. These data inform future potential approaches aimed at blocking surgically induced immunosuppression that might improve the outcomes of intraoperative combined modality treatment.SignificanceAlthough mesothelioma is difficult to treat, we have shown that combining surgery with a form of radiation, photodynamic therapy, may help people with mesothelioma live longer. In this study, we demonstrate in mice that this regimen could be further improved by addressing the inflammation induced as a by-product of surgery.

Dataset Information

Intestinal inflammation alters the antigen-specific immune response to a skin commensal.

Publications

Intestinal inflammation alters the antigen-specific immune response to a skin commensal.

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