An effective resolution program may be able to prevent the progression from non-resolving acute inflammation to persistent chronic inflammation. It has now become evident that coordinated resolution programs initiate shortly after inflammatory responses begin. In this context, several mechanisms provide the fine-tuning of inflammation and create a favorable environment for the resolution phase to take place and for homeostasis to return. In this review, we focus on the events required for an effective transition from the proinflammatory phase to the onset and establishment of resolution. We suggest that several mediators that promote the inflammatory phase of inflammation can simultaneously initiate a program for active resolution. Indeed, several events enact a decrease in the local chemokine concentration, a reduction which is essential to inhibit further infiltration of neutrophils into the tissue. Interestingly, although neutrophils are cells that characteristically participate in the active phase of inflammation, they also contribute to the onset of resolution. Further understanding of the molecular mechanisms that initiate resolution may be instrumental to develop pro-resolution strategies to treat complex chronic inflammatory diseases in humans. The efforts to develop strategies based on resolution of inflammation have shaped a new area of pharmacology referred to as ‘resolution pharmacology’.

The spread of SARS-CoV-2 in Brazil: Brazil has been hard-hit by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Candido et al. combined genomic and epidemiological analyses to investigate the impact of nonpharmaceutical interventions (NPIs) in the country. By setting up a network of genomic laboratories using harmonized protocols, the researchers found a 29% positive rate for SARS-CoV-2 among collected samples. More than 100 international introductions of SARS-CoV-2 into Brazil were identified, including three clades introduced from Europe that were already well established before the implementation of NPIs and travel bans. The virus spread from urban centers to the rest of the country, along with a 25% increase in the average distance traveled by air passengers before travel bans, despite an overall drop in short-haul travel. Unfortunately, the evidence confirms that current interventions remain insufficient to keep virus transmission under control in Brazil. Science , this issue p. 1255

BackgroundChronic heart failure is one of a number of disorders associated with the development of a wasting syndrome. The precise mechanisms of this

The ability of an individual to sense pain is fundamental for its capacity to adapt to its environment and to avoid damage. The sensation of pain can be enhanced by acute or chronic inflammation. In the present study, we have investigated whether inflammatory pain, as measured by hypernociceptive responses, was modified in the absence of the microbiota. To this end, we evaluated mechanical nociceptive responses induced by a range of inflammatory stimuli in germ-free and conventional mice. Our experiments show that inflammatory hypernociception induced by carrageenan, lipopolysaccharide, TNF-α, IL-1β, and the chemokine CXCL1 was reduced in germ-free mice. In contrast, hypernociception induced by prostaglandins and dopamine was similar in germ-free or conventional mice. Reduction of hypernociception induced by carrageenan was associated with reduced tissue inflammation and could be reversed by reposition of the microbiota or systemic administration of lipopolysaccharide. Significantly, decreased hypernociception in germ-free mice was accompanied by enhanced IL-10 expression upon stimulation and could be reversed by treatment with an anti-IL-10 antibody. Therefore, these results show that contact with commensal microbiota is necessary for mice to develop inflammatory hypernociception. These findings implicate an important role of the interaction between the commensal microbiota and the host in favoring adaptation to environmental stresses, including those that cause pain.

Objective: Deposition of monosodium urate monohydrate (MSU) crystals in the joints promotes an intense inflammatory response and joint dysfunction. This study evaluated the role of the NLRP3 inflammasome and 5‐lipoxygenase (5‐LOX)–derived leukotriene B₄(LTB₄) in driving tissue inflammation and hypernociception in a murine model of gout.Methods: Gout was induced by injecting MSU crystals into the joints of mice. Wild‐type mice and mice deficient in NLRP3, ASC, caspase 1, interleukin‐1β (IL‐1β), IL‐1 receptor type I (IL‐1RI), IL‐18R, myeloid differentiation factor 88 (MyD88), or 5‐LOX were used. Evaluations were performed to assess neutrophil influx, LTB₄activity, cytokine (IL‐1β, CXCL1) production (by enzyme‐linked immunosorbent assay), synovial microvasculature cell adhesion (by intravital microscopy), and hypernociception. Cleaved caspase 1 and production of reactive oxygen species (ROS) were analyzed in macrophages by Western blotting and fluorometric assay, respectively.Results: Injection of MSU crystals into the knee joints of mice induced neutrophil influx and neutrophil‐dependent hypernociception. MSU crystal–induced neutrophil influx was CXCR2‐dependent and relied on the induction of CXCL1 in an NLRP3/ASC/caspase 1/IL‐1β/MyD88–dependent manner. LTB₄was produced rapidly after injection of MSU crystals, and this was necessary for caspase 1–dependent IL‐1β production and consequent release of CXCR2‐acting chemokines in vivo. In vitro, macrophages produced LTB₄after MSU crystal injection, and LTB₄was relevant in the MSU crystal–induced maturation of IL‐1β. Mechanistically, LTB₄drove MSU crystal–induced production of ROS and ROS‐dependent activation of the NLRP3 inflammasome.Conclusion: These results reveal the role of the NLRP3 inflammasome in mediating MSU crystal–induced inflammation and dysfunction of the joints, and highlight a previously unrecognized role of LTB₄in driving NLRP3 inflammasome activation in response to MSU crystals, both in vitro and in vivo.