CD8+ T cell cytotoxicity mediates pathology in the skin by inflammasome activation and IL-1β production

Abstract

Deregulated CD8+ T cell cytotoxicity plays a central role in enhancing disease severity in several conditions. However, we have little understanding of the mechanisms by which immunopathology develops as a consequence of cytotoxicity. Using murine models of inflammation induced by the protozoan parasite leishmania, and data obtained from patients with cutaneous leishmaniasis, we uncovered a previously unrecognized role for NLRP3 inflammasome activation and IL-1β release as a detrimental consequence of CD8+ T cell-mediated cytotoxicity, ultimately resulting in chronic inflammation. Critically, pharmacological blockade of NLRP3 or IL-1β significantly ameliorated the CD8+ T cell-driven immunopathology in leishmania-infected mice. Confirming the relevance of these findings to human leishmaniasis, blockade of the NLRP3 inflammasome in skin biopsies from leishmania-infected patients prevented IL-1β release. Thus, these studies link CD8+ T cell cytotoxicity with inflammasome activation and reveal novel avenues of treatment for cutaneous leishmaniasis, as well as other of diseases where CD8+ T cell-mediated cytotoxicity induces pathology.

Macrophage priming is dispensable for NLRP3 inflammasome activation and restriction of Leishmania amazonensis replication

“…By employing different techniques and approaches to assess inflammasome activation, we provide significant results explaining long‐standing questions regarding the requirement of external priming to study IL‐1β release and inflammasome activation in response to Leishmania spp in vitro. Importantly, in the light of the critical role of NLRP3 in the outcome of Leishmaniasis, this study opens venues for further investigation of the key macrophage processes related to NLRP3 activation in resident macrophages in vivo.…”

“…However, priming isolated cells prior infection is a common strategy to boost gene regulation and to synchronize inflammasome activation upon infection with many microbes including parasites, bacteria, and viruses . It is important to highlight that, in vivo, Leishmania parasites activate the inflammasome without the requirement of priming or LPS injection . We believe that this occur because of tissue damage caused during infection, the release of alarmins, such as ATP, IL‐1α, and high mobility group box 1 (HMGB1), and also other inflammatory mediators such as IFN‐γ and TNF‐α, which can boost NF‐κB signaling and are extremely important in the pathogenesis of Leishmania infections .…”

“…26,[45][46][47][48] It is important to highlight that, in vivo, Leishmania parasites activate the inflammasome without the requirement of priming or LPS injection. 25,27,29,49 We believe that this occur because of tissue damage caused during infection, the release of alarmins, such as ATP, IL-1 , and high mobility group box 1 (HMGB1), and also other inflammatory mediators such as IFN-and TNF-, which can boost NF-B signaling and are extremely important in the pathogenesis of Leishmania infections. 9,24,50 In addition, it is also possible that bacterial co-infection in the cutaneous Leishmania lesions present in patients favor the priming of myeloid cells during Leishmania infections in vivo.…”

Compartmentalized cytotoxic immune response leads to distinct pathogenic roles of natural killer and senescent CD8+ T cells in human cutaneous leishmaniasis

“…In cutaneous leishmaniasis (CL), a good prognosis is related to the predominance of a cellular T helper type 1 (Th1) response with production of interferon‐ γ , tumour necrosis factor‐ α (TNF‐ α ) and activation of parasite‐infected macrophages. On the other hand, the exacerbated Th1 immunity and cytotoxic response were identified as key elements in the immunopathogenesis of both murine and human CL caused by L. braziliensis . The gene expression analysis in CL skin lesions revealed that cytotoxicity‐related genes are overexpressed compared with the cytokine pathway, representing the main signature of L. braziliensis infection.…”

“…On the other hand, the exacerbated Th1 immunity and cytotoxic response were identified as key elements in the immunopathogenesis of both murine and human CL caused by L. braziliensis. [2][3][4][5] The gene expression analysis in CL skin lesions revealed that cytotoxicity-related genes are overexpressed compared with the cytokine pathway, 6 representing the main signature of L. braziliensis infection. In patients with CL, the accumulation of cytotoxic CD8 + T cells or granzyme B-producing cells was linked with the severity of CL.…”