Sensing soluble uric acid by Naip1-Nlrp3 platform

Uric acid (UA), a product of purine nucleotide degradation able to initiate an immune response, represents a breakpoint in the evolutionary history of humans, when uricase, the enzyme required for UA cleavage, was lost. Despite being inert in human cells, UA in its soluble form (sUA) can increase the level of interleukin-1beta (IL-1beta) in murine macrophages. We, therefore, hypothesized that the recognition of sUA is achieved by the Naip1-Nlrp3 inflammasome platform. Through structural modelling predictions and transcriptome and functional analyses, we found that murine Naip1 expression in human macrophages induces IL-1beta expression, fatty acid production and an inflammation-related response upon sUA stimulation, a process reversed by the pharmacological and genetic inhibition of Nlrp3. Moreover, molecular interaction experiments showed that Naip1 directly recognizes sUA. Accordingly, Naip may be the sUA receptor lost through the human evolutionary process, and a better understanding of its recognition may lead to novel anti-hyperuricaemia therapies

Editorial: Macrophages role in integrating tissue Signals and Biological Processes in Chronic inflammation and Fibrosis

Univ Sao Paulo, Immunol Dept, Sao Paulo, BrazilINSERM, Paris, FranceUniv Fed Sao Paulo, Nephrol Div, Med Dept, Sao Paulo, BrazilUniv Sao Paulo, Renal Physiol Lab, Fac Med, Sao Paulo, BrazilUniv Fed Sao Paulo, Nephrol Div, Med Dept, Sao Paulo, BrazilWeb of Scienc

The dual effect of acetate on microglial TNF-α production

Introduction: Short-Chain Fatty Acids (SCFA) are products of intestinal microbial metabolism that can reach the brain and alter microglia in health and disease contexts. However, data are conflicting on the effect of acetate, the most abundant SCFA in the blood, in these cells. Objective: The authors aimed to investigate acetate as a modulator of the inflammatory response in microglia stimulated with LPS. Method: The authors used an immortalized cell line, C8-B4, and primary cells for in vitro treatments with acetate and LPS. Cell viability was analyzed by MTT, cytokine by RT-PCR, ELISA, and flow cytometry. The authors also performed in vivo and in silico analyses to study the role of acetate and the TNF-α contribution to the development of Experimental Autoimmune Encephalomyelitis (EAE). Results: Acetate co-administered with LPS was able to exacerbate the production of pro-inflammatory cytokines at gene and protein levels in cell lines and primary culture of microglia. However, the same effects were not observed when acetate was administered alone or as pretreatment, prior to the LPS stimulus. Additionally, pharmacological inhibition of histone deacetylase concomitantly with acetate and LPS led to decreased TNF-α production. In silico analysis showed a crucial role of the TNF-α pathway in EAE development. Moreover, acetate administration in vivo during the initial phase of EAE led to a better disease outcome and reduced TNF-α production. Conclusion: Treatment with acetate was able to promote the production of TNF-α in a concomitant LPS stimulus of microglia. However, the immune modulation of microglia by acetate pretreatment may be a component in the generation of future therapies for neurodegenerative diseases

Macrophage Trafficking as Key Mediator of Adenine-Induced Kidney Injury

Macrophages play a special role in the onset of several diseases, including acute and chronic kidney injuries. in this sense, tubule interstitial nephritis (TIN) represents an underestimated insult, which can be triggered by different stimuli and, in the absence of a proper regulation, can lead to fibrosis deposition. Based on this perception, we evaluated the participation of macrophage recruitment in the development of TIN. Initially, we provided adenine-enriched food to WT and searched for macrophage presence and action in the kidney. Also, a group of animals were depleted of macrophages with the clodronate liposome while receiving adenine-enriched diet. We collected blood and renal tissue from these animals and renal function, inflammation, and fibrosis were evaluated. We observed higher expression of chemokines in the kidneys of adenine-fed mice and a substantial protection when macrophages were depleted. Then, we specifically investigated the role of some key chemokines, CCR5 and CCL3, in this TIN experimental model. Interestingly, CCR5 KO and CCL3 KO animals showed less renal dysfunction and a decreased proinflammatory profile. Furthermore, in those animals, there was less profibrotic signaling. in conclusion, we can suggest that macrophage infiltration is important for the onset of renal injury in the adenine-induced TIN.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Instituto Nacional de Ciencia e Tecnologia de Fluidos Complexos (INCT Complex Fluids)Univ São Paulo, Inst Biomed Sci, Dept Immunol, Lab Transplantat Immunobiol, BR-05508900 São Paulo, BrazilUniversidade Federal de São Paulo, Div Nephrol, Lab Clin & Expt Immunol, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, BR-04023062 São Paulo, BrazilUniv São Paulo, Inst Chem, Dept Biochem, BR-05508000 São Paulo, BrazilUniv São Paulo, Sch Med Ribeirao Preto, Dept Biochem & Immunol, BR-14049900 Ribeirao Preto, SP, BrazilUniversidade Federal de São Paulo, Div Nephrol, Lab Clin & Expt Immunol, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, BR-04023062 São Paulo, BrazilFAPESP: 2009/54474-8FAPESP: 2012/02270-2FAPESP: 2013/25010-9Web of Scienc

Understanding the Metabolic Profile of Macrophages During the Regenerative Process in Zebrafish

In contrast to mammals, lower vertebrates, including zebrafish (Danio rerio), have the ability to regenerate damaged or lost tissues, such as the caudal fin, which makes them an ideal model for tissue and organ regeneration studies. Since several diseases involve the process of transition between fibrosis and tissue regeneration, it is necessary to attain a better understanding of these processes. It is known that the cells of the immune system, especially macrophages, play essential roles in regeneration by participating in the removal of cellular debris, release of pro- and anti-inflammatory factors, remodeling of components of the extracellular matrix and alteration of oxidative patterns during proliferation and angiogenesis. Immune cells undergo phenotypical and functional alterations throughout the healing process due to growth factors and cytokines that are produced in the tissue microenvironment. However, some aspects of the molecular mechanisms through which macrophages orchestrate the formation and regeneration of the blastema remain unclear. In the present review, we outline how macrophages orchestrate the regenerative process in zebrafish and give special attention to the redox balance in the context of tail regeneration

Dectin-1 Activation Exacerbates Obesity and Insulin Resistance in the Absence of MyD88

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, grant numbers 11/15682-4, 12/02270-2, 15/18121-4), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Regenera INCT Process Grant 465656/2014-5). JL is funded by the NIH/NIDDK R01DK106210. GDB is funded by the Wellcome Trust and the MRC Centre for Medical Mycology. Open access journalPeer reviewedPublisher PD

TLR2, TLR4 and the MYD88 Signaling Pathway Are Crucial for Neutrophil Migration in Acute Kidney Injury Induced by Sepsis

The aim of this study was to investigate the role of TLR2, TLR4 and MyD88 in sepsis-induced AKI. C57BL/6 TLR2(-/-), TLR4(-/-) and MyD88(-/-) male mice were subjected to sepsis by cecal ligation and puncture (CLP). Twenty four hours later, kidney tissue and blood samples were collected for analysis. the TLR2(-/-), TLR4(-/-) and MyD88(-/-) mice that were subjected to CLP had preserved renal morphology, and fewer areas of hypoxia and apoptosis compared with the wild-type C57BL/6 mice (WT). MyD88(-/-) mice were completely protected compared with the WT mice. We also observed reduced expression of proinflammatory cytokines in the kidneys of the knockout mice compared with those of the WT mice and subsequent inhibition of increased vascular permeability in the kidneys of the knockout mice. the WT mice had increased GR1(+low) cells migration compared with the knockout mice and decreased in GR1(+high) cells migration into the peritoneal cavity. the TLR2(-/-), TLR4(-/-), and MyD88(-/-) mice had lower neutrophil infiltration in the kidneys. Depletion of neutrophils in the WT mice led to protection of renal function and less inflammation in the kidneys of these mice. Innate immunity participates in polymicrobial sepsis-induced AKI, mainly through the MyD88 pathway, by leading to an increased migration of neutrophils to the kidney, increased production of proinflammatory cytokines, vascular permeability, hypoxia and apoptosis of tubular cells.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)National Institute of Science and Technology (INCT)Universidade Federal de São Paulo, Dept Med, Disciplina Nefrol, São Paulo, BrazilUniv São Paulo, Dept Imunol, Lab Imunobiol Transplantes, São Paulo, BrazilHosp Israelita Albert Einstein, IIEP, São Paulo, BrazilUniv Fed Triangulo Mineiro, Uberaba, BrazilUniversidade Federal de São Paulo, Dept Med, Disciplina Nefrol, São Paulo, BrazilFAPESP: 07/07139-3Web of Scienc

MyD88 Signaling Pathway Is Involved in Renal Fibrosis by Favoring a T(H)2 Immune Response and Activating Alternative M2 Macrophages

Inflammation contributes to the pathogenesis of chronic kidney disease (CKD). Molecules released by the inflamed injured tissue\ud can activate toll-like receptors (TLRs), thereby modulating macrophage and CD4+ T-cell activity. We propose that in renal fibrogenesis,\ud M2 macrophages are recruited and activated in a T helper subset 2 cell (TH2)-prone inflammatory milieu in a MyD88-\ud dependent manner. Mice submitted to unilateral ureteral ligation (UUO) demonstrated an increase in macrophage infiltration with\ud collagen deposition after 7 d. Conversely, TLR2, TLR4 and MyD88 knockout (KO) mice had an improved renal function together with\ud diminished TH2 cytokine production and decreased fibrosis formation. Moreover, TLR2, TLR4 and MyD88 KO animals exhibited less M2\ud macrophage infiltration, namely interleukin (IL)-10+ and CD206+ CD11bhigh cells, at 7 d after surgery. We evaluated the role of a TH2\ud cytokine in this context, and observed that the absence of IL-4 was associated with better renal function, decreased IL-13 and TGF-\ud β levels, reduced arginase activity and a decrease in fibrosis formation when compared with IL-12 KO and wild-type (WT) animals.\ud Indeed, the better renal outcomes and the decreased fibrosis formation were restricted to the deficiency of IL-4 in the hematopoietic\ud compartment. Finally, macrophage depletion, rather than the absence of T cells, led to reduced lesions of the glomerular filtration\ud barrier and decreased collagen deposition. These results provide evidence that future therapeutic strategies against renal\ud fibrosis should be accompanied by the modulation of the M1:M2 and TH1:TH2 balance, as TH2 and M2 cells are predictive of fibrosis\ud toward mechanisms that are sensed by innate immune response and triggered in a MyD88-dependent pathway.Brazilian Foundation - FAPESP (Fundacao de Apoio a Pesquisa do Estado de Sao Paulo) [07/07139-3, 10/52180-4]Brazilian Foundation FAPESP (Fundacao de Apoio a Pesquisa do Estado de Sao Paulo)International Associated Laboratory (CNPq/Inserm)International Associated Laboratory (CNPq/Inserm)National Institute of Science and Technology (INCT)National Institute of Science and Technology (INCT