Peritoneal inflammation remains a major cause of treatment failure in patients with kidney failure who receive peritoneal dialysis. Peritoneal inflammation is characterized by an increase in neutrophil infiltration. However, the molecular mechanisms that control neutrophil recruitment in peritonitis are not fully understood. ELMO and DOCK proteins form complexes which function as guanine nucleotide exchange factors to activate the small GTPase Rac to regulate F-actin dynamics during chemotaxis. In the current study, we found that deletion of the Elmo1 gene causes defects in chemotaxis and the adhesion of neutrophils. ELMO1 plays a role in the fMLP-induced activation of Rac1 in parallel with the PI3K and mTORC2 signaling pathways. Importantly, we also reveal that peritoneal inflammation is alleviated in Elmo1 knockout mice in the mouse model of thioglycollate-induced peritonitis. Our results suggest that ELMO1 functions as an evolutionarily conserved regulator for the activation of Rac to control the chemotaxis of neutrophils both in vitro and in vivo. Our results suggest that the targeted inhibition of ELMO1 may pave the way for the design of novel anti-inflammatory therapies for peritonitis.

Bone homeostasis is a metabolic balance between the new bone formation by osteoblasts and old bone resorption by osteoclasts. Excessive osteoclastic bone resorption results in low bone mass, which is the major cause of bone diseases such as rheumatoid arthritis. Small GTPases Rac1 is a key regulator of osteoclast differentiation, but its exact mechanism is not fully understood. ELMO and DOCK proteins form complexes that function as guanine nucleotide exchange factors for Rac activation. Here, we report that ELMO1 plays an important role in differentiation and bone resorption of osteoclasts. Osteoclast precursors derived from bone marrow monocytes (BMMs) of Elmo1^–/–mice display defective adhesion and migration during differentiation. The cells also have a reduced activation of Rac1, p38, JNK, and AKT in response to RANKL stimulation. Importantly, we show that bone erosion is alleviated in Elmo1^–/–mice in a rheumatoid arthritis mouse model. Taken together, our results suggest that ELMO1, as a regulator of Rac1, regulates osteoclast differentiation and bone resorption bothin vitroandin vivo.

Nailfold capillaroscopy is a reliable way to detect and analyze microvascular abnormalities. It is safe, simple, noninvasive, and inexpensive. Among all the capillaroscopic abnormalities, nailfold microhemorrhages are closely associated with early vascular damages and might be present in numerous diseases such as glaucoma, diabetes mellitus, and systemic sclerosis. Segmentation of nailfold microhemorrhages provides valuable pathological information that may lead to further investigations. A novel deep learning architecture named DAFM-Net is proposed for the accurate segmentation in this study. The network mainly consists of U-shape backbone, dual attention fusion module, and group normalization layer. The U-shape backbone generates rich hierarchical representations while the dual attention fusion module utilizes the captured features for fine adjustment. Group normalization is introduced as an effective normalization method to effectively improve the convergence ability of our deep neural network. The effectiveness of the proposed model is validated through ablation studies and segmentation experiments; the proposed method DAFM-Net achieves competitive performance for nailfold microhemorrhage segmentation with an IOU score of 78.03% and Dice score of 87.34% compared to the ground truth.