Regulation of tissue infiltration by neutrophils

Abstract

Purpose of review Neutrophils have traditionally been viewed in the context of acute infection and inflammation forming the first line of defence against invading pathogens. Neutrophil trafficking to the site of inflammation requires adhesion and transmigration through blood vessels, which is orchestrated by adhesion molecules, such as β2- and β1-integrins, chemokines and cytokines. This review focuses on recent advances in understanding the regulators of neutrophil recruitment during inflammation in both acute and chronic settings. Recent findings Recent findings suggest that besides the established pathways of selectin or chemokine-mediated integrin activation, signaling by distinct TLRs (especially TLR2, TLR4 and TLR5) can activate integrin-dependent neutrophil adhesion. Moreover, the integrin α3β1 has been vitally implicated as a new player in neutrophil recruitment and TLR-mediated responses in septic inflammation. Furthermore, several endogenous inhibitory mechanisms of leukocyte recruitment have been identified, including the secreted molecules Del-1, PTX3, and GDF-15, which block distinct steps of the leukocyte adhesion cascade, as well as novel regulatory signaling pathways, involving the protein kinase AKT1 and IFN-λ2/IL-28A. Summary The leukocyte adhesion cascade is a tightly regulated process, subjected to both positive and negative regulators. Dysregulation of this process and hence neutrophil recruitment can lead to the development of inflammatory and autoimmune diseases.

JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation

“…Expression levels of the 2 most prominent leukocyte integrins, β 1 and β 2 , were analyzed in the myeloid and lymphoid compartments of the bone marrow of JAK2 +/+ (Cre + ) and JAK2 +/VF (Cre + ) mice. β 1 (CD29) integrin expression was unchanged in granulocytes of JAK2 +/VF compared with JAK2 +/+ mice, corroborating previously published results in human granulocytes isolated from JAK2-and inflammation (18)(19)(20)(21)(22)(23). Two major integrin β-chains, β 1 and β 2 , are expressed on leukocytes, forming either VLA-4 (very late antigen-4) or LFA-1 (lymphocyte function-associated antigen-1) (19).…”

“…Thus, our findings identified cross-talk between JAK2-V617F and integrin activation promoting pathologic thrombosis and abnormal trafficking of leukocytes to the spleen. JAK2-V617F promotes venous thrombosis through β 1 /β 2 integrin activation migration across the physical endothelium/extracellular matrix (ECM) barrier, and homing of leukocytes into tissues (18)(19)(20)(21)(22)(23). We hypothesized that abnormal function of integrins on leukocytes, in particular neutrophils, may induce abnormal leukocyte-endothelium interaction and thus may contribute to pathologic thrombosis in CMN.…”

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

“…A growing body of research suggests that β2 integrins play an important role in tolerance induction [247][248][249] and suppression of inflammation [83,250,251]. Already decades ago, it was noted that LAD-I patients suffer not only from bacterial infections but also from renal or intestinal autoimmune diseases [252,253], and some of them presented type 1 diabetes or autoimmune cytopenia after hematopoietic stem cell transplantation [254].…”

From leukocyte recruitment to resolution of inflammation: the cardinal role of integrins

“…Specifically, the interaction of integrins LFA-1 and Mac-1 with ICAM-1 enables neutrophil crawling onto pericytes in the context of extravasation through the venular wall [42]. Finally, a3b1 (CD49c/CD29) integrin and its interacting ligands were recently shown to promote neutrophil extravasation in sepsis [43,44].…”