NLRP3 gain-of-function in CD4+ T lymphocytes ameliorates experimental autoimmune encephalomyelitis

Abstract

NLRP3 inflammasome [NLR (nucleotide-binding domain, leucine-rich repeat containing protein) Pyrin-domain-containing 3 ] functions as an innate sensor of several PAMPs and DAMPs (pathogen- and damage-associated molecular patterns). It has been also reported as a transcription factor related to Th2 pattern, although its role in the adaptive immunity has been controversial, mainly because the studies were performed using gene deletion approaches. In the present study, we have investigated the NLRP3 gain-of-function in the context of encephalomyelitis autoimmune disease (EAE), considered to be a Th1- and Th17-mediated disease. We took advantage of an animal model with NLRP3 gain-of-function exclusively to T CD4+ lymphocytes (CD4CreNLRP3fl/fl). These mice presented reduced clinical score, accompanied by less infiltrating T CD4+ cells expressing both IFN-γ and IL-17 at the central nervous system (CNS) during the peak of the disease. However, besides NLRP3 gain-of-function in lymphocytes, these mice lack NLRP3 expression in non-T CD4+ cells. Therefore, in order to circumvent this deficiency, we transferred naive CD4+ T cells from WT, NLRP3−/− or CD4CreNLRP3fl/fl into Rag-1−/− mice and immunized them with MOG35–55. Likewise, the animals repopulated with CD4CreNLRP3fl/fl T CD4+ cells presented reduced clinical score and decreased IFN-γ production at the peak of the disease. Additionally, primary effector CD4+ T cells derived from these mice presented reduced glycolytic profile, a metabolic profile compatible with Th2 cells. Finally, naive CD4+ T cells from CD4CreNLRP3fl/fl mice under a Th2-related cytokine milieu cocktail exhibited in vitro an increased IL-4 and IL-13 production. Conversely, naive CD4+ T cells from CD4CreNLRP3fl/fl mice under Th1 differentiation produced less IFN-γ and T-bet. Altogether, our data evidence that the NLRP3 gain-of-function promotes a Th2-related response, a pathway that could be better explored in the treatment of multiple sclerosis.

Transcriptional profiling identifies caspase-1 as a T cell–intrinsic regulator of Th17 differentiation

“…However, consistent with our data, recent work has shown that ASC-caspase-8 inflammasome, rather than caspase-1, is activated during pathogenic Th17 generation (Martin et al, 2016). Interestingly, NLRP3 has been reported to promote Th2 differentiation independently of the inflammasome (Bruchard et al, 2015; Braga et al, 2019), hinting at standalone functions for proteins that have been implicated in inflammasome activation. Overall, these data provide compelling evidence that caspase-1 promotes Th17 differentiation in an inflammasome-independent manner.…”

CARD8 inflammasome activation triggers pyroptosis in human T cells

“…An alternative second line of research proposes that inflammasome components or caspase‐1 itself exert functions in T cells beyond their conventional roles. To this end, it has been shown that NLRP3 functions as a transcriptional regulator of Th2 differentiation as evidenced in a loss‐of‐function (Bruchard et al , ) or gain‐of‐function setting (Braga et al , ). Adding to this, a recent study suggests that caspase‐1 plays a critical role in Th17 differentiation, independent of its catalytic activity (Gao et al , ).…”

Bixin Attenuates Experimental Autoimmune Encephalomyelitis by Suppressing TXNIP/NLRP3 inflammasome Activity and Activating Nrf2 Signaling

“…The TXNIP/NLRP3 in ammasome plays a key role in the pathogenesis of various diseases [30,32,34,35]. Chen W et al [9] have indicated that minocycline improves diabetic retinopathy by inhibiting the TXNIP/NLRP3 in ammasome pathway, and Vitamin D3 attenuates diabetic retinopathy by inhibiting high-glucose-induced ROS/TXNIP/NLRP3 in ammasome pathway [36].…”