Integrins in Health and Disease

Recognition for Integrin ResearchThis year's Lasker Basic Medical Research Award goes to Drs. Hynes, Ruoslahti, and Springer for their discovery and characterization of a major class of adhesion molecules: the integrins.Peer reviewe

Kindlin-3 in the immune system

Kindlin-3 is a member of the kindlin family of focal adhesion proteins which bind to integrin beta-chain cytoplasmic domains to regulate integrin function. In contrast to kindlin-1 and kindlin-2 proteins, kindlin-3 is expressed mainly in the hematopoietic system. Mutations in kindlin-3 result in the rare genetic disorder, leukocyte adhesion deficiency type III (LAD-III), which is characterized by bleeding and recurrent infections due to deficient beta1, beta2 and beta3 integrin activation in platelets and leukocytes. Here, we review the role of kindlin-3 in integrin activation and in different immune cell functions

Beta2-Integrins and Interacting Proteins in Leukocyte Trafficking, Immune Suppression, and Immunodeficiency Disease

Beta2-integrins are complex leukocyte-specific adhesion molecules that are essential for leukocyte (e.g., neutrophil, lymphocyte) trafficking, as well as for other immunological processes such as neutrophil phagocytosis and ROS production, and T cell activation. Intriguingly, however, they have also been found to negatively regulate cytokine responses, maturation, and migratory responses in myeloid cells such as macrophages and dendritic cells, revealing new, and unexpected roles of these molecules in immunity. Because of their essential role in leukocyte function, a lack of expression or function of beta2-integrins causes rare immunodeficiency syndromes, Leukocyte adhesion deficiency type I, and type III (LAD-I and LAD-III). LAD-I is caused by reduced or lost expression of beta2-integrins, whilst in LAD-III, beta2-integrins are expressed but dysfunctional because a major integrin cytoplasmic regulator, kindlin-3, is mutated. Interestingly, some LAD-related phenotypes such as periodontitis have recently been shown to be due to an uncontrolled inflammatory response rather than to an uncontrolled infection, as was previously thought. This review will focus on the recent advances concerning the regulation and functions of beta2-integrins in leukocyte trafficking, immune suppression, and immune deficiency disease.Peer reviewe

Molecular Mechanisms of Leukocyte Migration and Its Potential Targeting-Lessons Learned From MKL1/SRF-Related Primary Immunodeficiency Diseases

Megakaryoblastic leukemia 1 (MKL1) deficiency is one of the most recently discovered primary immunodeficiencies (PIDs) caused by cytoskeletal abnormalities. These immunological "actinopathies" primarily affect hematopoietic cells, resulting in defects in both the innate immune system (phagocyte defects) and adaptive immune system (T-cell and B-cell defects). MKL1 is a transcriptional coactivator that operates together with serum response factor (SRF) to regulate gene transcription. The MKL/SRF pathway has been originally described to have important functions in actin regulation in cells. Recent results indicate that MKL1 also has very important roles in immune cells, and that MKL1 deficiency results in an immunodeficiency affecting the migration and function of primarily myeloid cells such as neutrophils. Interestingly, several actinopathies are caused by mutations in genes which are recognized MKL(1/2)-dependent SRF-target genes, namely ACTB, WIPF1, WDR1, and MSN. Here we summarize these and related (ARPC1B) actinopathies and their effects on immune cell function, especially focusing on their effects on leukocyte adhesion and migration. Furthermore, we summarize recent therapeutic efforts targeting the MKL/SRF pathway in disease.Peer reviewe

beta 2 Integrin Signaling Cascade in Neutrophils : More Than a Single Function

Neutrophils are the most prevalent leukocytes in the human body. They have a pivotal role in the innate immune response against invading bacterial and fungal pathogens, while recent emerging evidence also demonstrates their role in cancer progression and anti-tumor responses. The efficient execution of many neutrophil effector responses requires the presence of beta 2 integrins, in particular CD11a/CD18 or CD11b/CD18 heterodimers. Although extensively studied at the molecular level, the exact signaling cascades downstream of beta 2 integrins still remain to be fully elucidated. In this review, we focus mainly on inside-out and outside-in signaling of these two beta 2 integrin members expressed on neutrophils and describe differences between various neutrophil stimuli with respect to integrin activation, integrin ligand binding, and the pertinent differences between mouse and human studies. Last, we discuss how integrin signaling studies could be used to explore the therapeutic potential of targeting beta 2 integrins and the intracellular signaling cascade in neutrophils in several, among other, inflammatory conditions in which neutrophil activity should be dampened to mitigate disease.Peer reviewe

Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status

Rationale: The diabetes drug metformin is under investigation in cardiovascular disease but the molecular mechanisms underlying possible benefits are poorly understood. Objective: Here we have studied anti-inflammatory effects of the drug and their relationship to anti-hyperglycaemic properties. Methods and Results: In primary hepatocytes from healthy animals, metformin and the IKKβ inhibitor BI605906 both inhibited TNFα-dependent IκB degradation and expression of pro-inflammatory mediators IL-6, IL-1b, and CXCL1/2. Metformin suppressed IKKα/β activation, an effect which could be separated from some metabolic actions, in that BI605906 did not mimic effects of metformin on lipogenic gene expression, glucose production and AMPK activation. Equally AMPK was not required either for mitochondrial suppression of IκB degradation. Consistent with discrete anti-inflammatory actions, in macrophages metformin specifically blunted secretion of pro-inflammatory cytokines, without inhibiting M1/M2 differentiation or activation. In a large treatment naïve diabetes population cohort, we observed differences in the systemic inflammation marker, Neutrophil to Lymphocyte Ratio (NLR), following incident treatment with either metformin or sulfonylurea monotherapy. Compared to sulfonylurea exposure, metformin reduced the mean log-transformed NLR after 8-16 months by 0.09 units (95% CI=0.02-0.17, p=0.013), and increased the likelihood that NLR would be lower than baseline after 8-16 months (OR 1.83, 95% CI=1.22-2.75, p=0.00364). Following up these findings in a double blind placebo controlled trial in nondiabetic heart failure (trial registration: NCT00473876), metformin suppressed plasma cytokines including the ageing-associated cytokine CCL11. Conclusions: We conclude that anti-inflammatory properties of metformin are exerted irrespective of diabetes status. This may accelerate investigation of drug utility in non-diabetic cardiovascular disease groups

Mice Lacking beta2-Integrin Function Remain Glucose Tolerant in Spite of Insulin Resistance, Neutrophil Infiltration and Inflammation

Beta2-integrins are important in leukocyte trafficking and function, and are regulated through the binding of cytoplasmic proteins, such as kindlin-3, to their intracellular domain. Here, we investigate the involvement of beta2-integrins in the regulation of metabolic disease using mice where the kindlin-3 binding site in the beta2-integrin cytoplasmic tail has been mutated (TTT/AAA-beta2-integrin knock-in (KI) mice), leading to expressed but dysfunctional beta2-integrins and significant neutrophilia in vivo. Beta2-integrin KI mice fed on a high fat diet showed normal weight gain, and normal accumulation of macrophages and lymphocytes in white adipose tissue (WAT) and liver, but increased neutrophil numbers especially in WAT. In addition, beta2-integrin KI mice fed on a high fat diet showed significantly increased peripheral insulin resistance in response to high-fat feeding. However, this was associated with improved glucose disposal following glucose load. Interestingly, beta2-integrin KI neutrophils produced more elastase in vitro, in response to stimulation. Beta2-integrin KI mice displayed variability of tissue inflammatory status, with liver and WAT exhibiting little or no difference in inflammation compared to high fat fed controls, whereas skeletal muscle demonstrated a raised inflammatory profile in association with higher elastase levels and diminished signalling through the IRS1-PKB pathway. In conclusion, although expression of dysfunctional beta2-integrins increased neutrophil production and infiltration into tissue, skeletal muscle was the most affected tissue exhibiting evidence of higher neutrophil activity and insulin resistance. Thus, beta2-integrins modulate glucose homeostasis during high fat feeding predominantly through actions on skeletal muscle to affect metabolic phenotype in vivo.Peer reviewe