Explore the vast range of titles available.

Genetic and pharmacological inhibition of the high-affinity LTB4 receptor promotes improved metabolism in obese mice. Insulin resistance results from several pathophysiologic mechanisms, including chronic tissue inflammation and defective insulin signaling. We found that liver, muscle and adipose tissue exhibit higher levels of the chemotactic eicosanoid LTB4 in obese high-fat diet (HFD)–fed mice. Inhibition of the LTB4 receptor Ltb4r1, through either genetic or pharmacologic loss of function, led to an anti-inflammatory phenotype with protection from insulin resistance and hepatic steatosis. In vitro treatment with LTB4 directly enhanced macrophage chemotaxis, stimulated inflammatory pathways, reduced insulin-stimulated glucose uptake in L6 myocytes, and impaired insulin-mediated suppression of hepatic glucose output in primary mouse hepatocytes. This was accompanied by lower insulin-stimulated Akt phosphorylation and higher Irs-1/2 serine phosphorylation, and all of these events were dependent on Gαi and Jnk1, two downstream mediators of Ltb4r1 signaling. These observations elucidate a novel role of the LTB4–Ltb4r1 signaling pathway in hepatocyte and myocyte insulin resistance, and they show that in vivo inhibition of Ltb4r1 leads to robust insulin-sensitizing effects.

Tissue inflammation is a key component of obesity-induced insulin resistance, with a variety of immune cell types accumulating in adipose tissue. Here, we have demonstrated increased numbers of B2 lymphocytes in obese adipose tissue and have shown that high-fat diet-induced (HFD-induced) insulin resistance is mitigated in B cell-deficient (Bnull) mice. Adoptive transfer of adipose tissue B2 cells (ATB2) from wild-type HFD donor mice into HFD Bnull recipients completely restored the effect of HFD to induce insulin resistance. Recruitment and activation of ATB2 cells was mediated by signaling through the chemokine leukotriene B4 (LTB4) and its receptor LTB4R1. Furthermore, the adverse effects of ATB2 cells on glucose homeostasis were partially dependent upon T cells and macrophages. These results demonstrate the importance of ATB2 cells in obesity-induced insulin resistance and suggest that inhibition of the LTB4/LTB4R1 axis might be a useful approach for developing insulin-sensitizing therapeutics.

Neutrophil recruitment into the joint is a hallmark of inflammatory arthritides, including rheumatoid arthritis (RA). In a mouse model of autoantibody-induced inflammatory arthritis, neutrophils infiltrate the joint via multiple chemoattractant receptors, including the leukotriene B ₄ (LTB ₄) receptor BLT1 and the chemokine receptors CCR1 and CXCR2. Once in the joint, neutrophils perpetuate their own recruitment by releasing LTB ₄ and IL-1β, presumably after activation by immune complexes deposited on joint structures. Two pathways by which immune complexes may activate neutrophils include complement fixation, resulting in the generation of C5a, and direct engagement of Fcγ receptors (FcγRs). Previous investigations showed that this model of autoantibody-induced arthritis requires the C5a receptor C5aR and FcγRs, but the simultaneous necessity for both pathways was not understood. Here we show that C5aR and FcγRs work in sequence to initiate and sustain neutrophil recruitment in vivo. Specifically, C5aR activation of neutrophils is required for LTB ₄ release and early neutrophil recruitment into the joint, whereas FcγR engagement upon neutrophils induces IL-1β release and subsequent neutrophil-active chemokine production, ensuring continued inflammation. These findings support the concept that immune complex-mediated leukocyte activation is not composed of overlapping and redundant pathways, but that each element serves a distinct and critical function in vivo, culminating in tissue inflammation.

IgA antibodies play an important role in mucosal immunity. However, there is still no effective way to consistently boost mucosal IgA responses, and the factors influencing these responses are not fully understood. We observed that colonization with the murine intestinal symbiotic protozoan Tritrichomonas musculis ( T.mu ) boosted antigen-specific mucosal IgA responses in wild-type C57BL/6 mice. This enhancement was attributed to the accumulation of free arachidonic acid (ARA) in the intestinal lumen, which served as a signal to stimulate the production of antigen-specific mucosal IgA. When ARA was prevented from undergoing its downstream metabolic transformation using the 5-lipoxygenase inhibitor zileuton or by blocking its downstream biological signaling through genetic deletion of the Leukotriene B 4 receptor 1 ( Blt1 ), the T.mu -mediated enhancement of antigen-specific mucosal IgA production was suppressed. Moreover, both T.mu transfer and dietary supplementation of ARA augmented the efficacy of an oral vaccine against Salmonella infection, with this effect being dependent on Blt1. Our findings elucidate a tripartite circuit linking nutrients from the diet or intestinal microbiota, host lipid metabolism, and the mucosal humoral immune response. Immunoglobulin A (IgA) is an important part of the mucosal immune response. Here, the authors show that an intestinal commensal protist can enhance mucosal IgA production upon vaccination and that this involves the accumulation of free arachidonic acid in the intestinal lumen.

Leukotriene B4 (LTB4) receptor 1 (BLT1) is a G protein-coupled receptor expressed in various leukocyte subsets; however, the precise expression of mouse BLT1 (mBLT1) has not been reported because a mBLT1 monoclonal antibody (mAb) has not been available. In this study, we present the successful establishment of a hybridoma cell line (clone 7A8) that produces a high-affinity mAb for mBLT1 by direct immunization of BLT1-deficient mice with mBLT1-overexpressing cells. The specificity of clone 7A8 was confirmed using mBLT1-overexpressing cells and mouse peripheral blood leukocytes that endogenously express BLT1. Clone 7A8 did not cross-react with human BLT1 or other G protein-coupled receptors, including human chemokine (C-X-C motif) receptor 4. The 7A8 mAb binds to the second extracellular loop of mBLT1 and did not affect LTB4 binding or intracellular calcium mobilization by LTB4. The 7A8 mAb positively stained Gr-1-positive granulocytes, CD11b-positive granulocytes/monocytes, F4/80-positive monocytes, CCR2-high and CCR2-low monocyte subsets in the peripheral blood and a CD4-positive T cell subset, Th1 cells differentiated in vitro from naïve CD4-positive T cells. This mAb was able to detect Gr-1-positive granulocytes and monocytes in the spleens of naïve mice by immunohistochemistry. Finally, intraperitoneal administration of 7A8 mAb depleted granulocytes and monocytes in the peripheral blood. We have therefore succeeded in generating a high-affinity anti-mBLT1 mAb that is useful for analyzing mBLT1 expression in vitro and in vivo.

Bioactive matrix fragments (matrikines) have been identified in a myriad of disorders, but their impact on the evolution of airway inflammation has not been demonstrated. We recently described a pathway where the matrikine and neutrophil chemoattractant proline–glycine–proline (PGP) could be degraded by the enzyme leukotriene A 4 hydrolase (LTA 4 H). LTA 4 H classically functions in the generation of pro-inflammatory leukotriene B 4 , thus LTA 4 H exhibits opposing pro- and anti-inflammatory activities. The physiological significance of this secondary anti-inflammatory activity remains unknown. Here we show, using readily resolving pulmonary inflammation models, that loss of this secondary activity leads to more pronounced and sustained inflammation and illness owing to PGP accumulation. PGP elicits an exacerbated neutrophilic inflammation and protease imbalance that further degrades the extracellular matrix, generating fragments that perpetuate inflammation. This highlights a critical role for the secondary anti-inflammatory activity of LTA 4 H and thus has consequences for the generation of global LTA 4 H inhibitors currently being developed. Proteases degrade extracellular matrix during inflammation, releasing peptides that can recruit neutrophils. Here the authors show that degradation of such bioactive peptide by the enzyme leukotriene A4 hydrolase is critical to limit pulmonary inflammation during bacterial infection in mice.

Recent study has demonstrated that CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) present in bronchoalveolar lavage fluid (BALF) contribute to the resolution of an experimental acute lung injury (ALI). However, the molecular mechanism underlying the alveolar recruitment of Treg remains unclear. To determine the role of BLT1, a chemotactic receptor for leukotriene B4 (LTB4), in Treg recruitment to BALF of LPS-induced ALI. We examined BLT1 expression in mouse and human Tregs and evaluated its role in mediating Treg migration in vitro and in vivo. We found that BLT1 expression was strongly up-regulated in Tregs on activation, and that BLT1 mediated the migration of activated, but not resting, Tregs toward LTB4 in vitro. LTB4 levels were persistently elevated in BALF of LPS-induced ALI. Blockade of LTB4-BLT1 pathway by administrating antagonists 1 day after LPS exposure significantly decreased BALF Treg numbers and impaired resolution of ALI characterized by persistent BALF protein, neutrophilic infiltrates, and elevated proinflammatory cytokines. Furthermore, there were significantly less BLT1(-/-) Tregs than wild-type Tregs migrating to BALF of LPS-exposed recipient Rag-1(-/-) mice after adoptive transfer (point estimate 299.73; 95% confidence interval, 255.77-343.69; P < 0.00001), and the impaired alveolar recruitment of BLT1(-/-) Tregs caused the inability to restore the resolution of ALI. Our findings reveal a novel antiinflammatory role of BLT1 in the resolution of ALI by mediating the alveolar recruitment of Tregs, and indicate that therapies aimed at interrupting the LTB4-BLT1 pathway after ALI onset could be harmful to the resolution of ALI.

Leukotriene B 4 (LTB 4 ) is a potent chemoattractant for myeloid leukocytes, which express BLT1, the high-affinity receptor for LTB 4 . We report here that BLT1 is induced substantially in CD8 + effector T cells and at lower amounts in CD8 + central memory T cells. LTB 4 elicited BLT1-dependent chemotaxis in effector cells, but not in naive or central memory cells. Intravital microscopy showed that BLT1 signaling induced rapid integrin-mediated arrest of rolling effector and central memory cells in postcapillary venules. In competitive homing experiments, wild-type effector cells were three times more efficient at migrating to the inflamed peritoneal cavity than were BLT-deficient effector cells. These results identify LTB 4 -BLT1 as a potent nonchemokine pathway for cytotoxic effector cell traffic.

Studies in both humans and rodents indicate that CD8 + T cells may be important in allergic inflammation. However, neither the mechanisms that mediate CD8 + T cell recruitment to inflamed tissues nor the relative participation of effector and central memory CD8 + T cells is known. Here we report that activated mast cells induced chemotaxis of effector, but not central memory, CD8 + T cells through production of leukotriene B 4 (LTB 4 ). These studies indicate that LTB 4 production by activated peripheral leukocytes could be important for the recruitment of effector CD8 + T cells to sites of inflammation.

Leukotriene B 4 (LTB 4 ) was originally described as a potent lipid myeloid cell chemoattractant, rapidly generated from innate immune cells, that activates leukocytes through the G protein–coupled receptor BLT1. We report here that BLT1 is expressed on effector CD4 + T cells generated in vitro as well as in vivo when effector T cells migrate out of the lymphoid compartment and are recruited into peripheral tissues. BLT1 mediated LTB 4 -induced T helper type 1 (T H 1) and T H 2 cell chemotaxis and firm adhesion to endothelial cells under flow, as well as early CD4 + and CD8 + T cell recruitment into the airway in an asthma model. Our findings show that the LTB 4 -BLT1 pathway is involved in linking early immune system activation and early effector T cell recruitment.