Cell death induced by NLRP3-palmitate axis impairs pulmonary damage tolerance and aggravates immunopathology during obesity-tuberculosis comorbidity.

A low-grade and persistent inflammation, which is the hallmark of obesity, requires the participation of NLRP3 and cell death. During Mycobacterium tuberculosis infection, NLRP3 signaling is important for bacterial killing by macrophages in vitro but was shown to be dispensable for host protection in vivo. We hypothesized that during obesity-tuberculosis (TB) comorbidity, NLRP3 signaling might play a detrimental role by inducing excessive inflammation. We employed a model of high-fat-diet-induced obesity, followed by M. tuberculosis infection in C57BL/6 mice. Obese mice presented increased susceptibility to infection and pulmonary immunopathology compared to lean mice. Using treatment with NLRP3 antagonist and Nlrp3-/- mice, we showed that NLRP3 signaling promoted cell death, with no effect in bacterial loads. The levels of palmitate were higher in the lungs of obese infected mice compared to lean counterparts, and we observed that this lipid increased M. tuberculosis-induced macrophage death in vitro, which was dependent on NLRP3 and caspase-1. At the chronic phase, although lungs of obese Nlrp3-/- mice showed an indication of granuloma formation compared to obese wild-type mice, there was no difference in the bacterial load. Our findings indicate that NLRP3 may be a potential target for host-directed therapy to reduce initial and severe inflammation-mediated disease and to treat comorbidity-associated TB. © 2022 The Pathological Society of Great Britain and Ireland.

In search of mechanisms associated with mesenchymal stem cell-based therapies for acute kidney injury.

Acute kidney injury (AKI) is classically described as a rapid loss of kidney function. AKI affects more than 15% of all hospital admissions and is associated with elevated mortality rates. Although many advances have occurred, intermittent or continuous renal replacement therapies are still considered the best options for reversing mild and severe AKI syndrome. For this reason, it is essential that innovative and effective therapies, without side effects and complications, be developed to treat AKI and the end-stages of renal disease. Mesenchymal stem cell (MSC) based therapies have numerous advantages in helping to repair inflamed and damaged tissues and are being considered as a new alternative for treating kidney injuries. Numerous experimental models have shown that MSCs can act via differentiation-independent mechanisms to help renal recovery. Essentially, MSCs can secrete a pool of cytokines, growth factors and chemokines, express enzymes, interact via cell-to-cell contacts and release bioagents such as microvesicles to orchestrate renal protection. In this review, we propose seven distinct properties of MSCs which explain how renoprotection may be conferred: 1) anti-inflammatory; 2) pro-angiogenic; 3) stimulation of endogenous progenitor cells; 4) anti-apoptotic; 5) anti-fibrotic; 6) anti-oxidant; and 7) promotion of cellular reprogramming. In this context, these mechanisms, either individually or synergically, could induce renal protection and functional recovery. This review summarises the most important effects and benefits associated with MSC-based therapies in experimental renal disease models and attempts to clarify the mechanisms behind the MSC-related renoprotection. MSCs may prove to be an effective, innovative and affordable treatment for moderate and severe AKI. However, more studies need to be performed to provide a more comprehensive global understanding of MSC-related therapies and to ensure their safety for future clinical applications.

Avaliaçäo da imunidade periférica, pela técnica do linfonodo poplieteal após a injeçäo intratímica de antígenos do doador / Evaluation of peripherical immunity trough popliteal linfonode technic after intrathymic injection of donor antigens

A injeçäo intratímica (IT) é uma técnica eficiente nainduçäo de tolerância imunológica em modelos experimentais, nos quais se pode alcançar uma imunossupressäoespecífica sem comprometer o restante do sistema imune. Utilizou-se o modelo da técnica do linfonodo popliteal (TLP) para avaliar a resposta imune periférica aos aloantígenos previamente apresentados ao receptor pela IT. Camundongos entre 6 e 8 semanas, BALB/c (H2)foram usados como recptores. Esplenócitos foram isolados de camundongos DBA/2(H2), C57BL/6(H2) e C3H/He(H2), todos com a mesma faixa etária. A IT foi realizada7 dias do estímulo na pata (10 células). Os linfonodos foram retirados e pesados 7 dias após a TLP. Estímulo com células alogênicas aumentaram 3 vezes o peso do linfonodo quando comparado a células isogênicas (5,7+- 1,5 vs 2,6+-0,8p<0,001). IT com C57BL/6 reduziu as células C3H/He näo reduziram o peso do linfonodo subseqüente ao estímulo com C57BL/6 (8,9 +-3,4vc 5,7 +-1,7, p0,01. especificamente as células C3H/He näo reduziram o peso do linfonodo subseqüente ao estímulo com C57BL/6 (8,9 +-3,4 vs 5,7 +-1,5, p=0,08). A IT capaz de reduzir especificamente a resposta imune periférica aos aloantígenos verificada pela TLP