The Essential Involvement of the Omentum in the Peritoneal Defensive Mechanisms During Intra-Abdominal Sepsis

Although the abilities of the omentum to alleviate inflammation and prevent infection have been revealed over the past decades, the underlying mechanisms remain largely unelucidated. Here, we demonstrated that the mortality of mice exposed to cecal ligation and puncture (CLP) and omentectomy was remarkably increased compared to those treated with CLP alone. Moreover, the efficacy of the omentum was associated with an impairment in intraperitoneal bacterial clearance together with an increase in the expression of proinflammatory cytokines. Besides, in response to peritoneal infections, the size and quantity of the omental milky spots (MSs) were increased tremendously and they also support innate-like B1 cell responses and local IgM production in the peritoneal cavity. Furthermore, not only the migration but also the functional activities of neutrophils were diminished in the absence of the omentum. These data collectively show that the omentum contributes more to peritoneal immune responses during septic peritonitis than has heretofore been recognized. Thus, harnessing the function of MS-containing omentum to increase its protective effectiveness may exert important biological and therapeutic implications for the control of intra-abdominal infections.

Omental macrophages secrete chemokine ligands that promote ovarian cancer colonization of the omentum via CCR1

The omentum is the most common site of ovarian cancer metastasis. Immune cell clusters called milky spots are found throughout the omentum. It is however unknown if these immune cells contribute to ovarian cancer metastasis. Here we report that omental macrophages promote the migration and colonization of ovarian cancer cells to the omentum through the secretion of chemokine ligands that interact with chemokine receptor 1 (CCR1). We found that depletion of macrophages reduces ovarian cancer colonization of the omentum. RNA-sequencing of macrophages isolated from mouse omentum and mesenteric adipose tissue revealed a specific enrichment of chemokine ligand CCL6 in omental macrophages. CCL6 and the human homolog CCL23 were both necessary and sufficient to promote ovarian cancer migration by activating ERK1/2 and PI3K pathways. Importantly, inhibition of CCR1 reduced ovarian cancer colonization. These findings demonstrate a critical mechanism of omental macrophage induced colonization by ovarian cancer cells via CCR1 signaling.

Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum

Ovarian cancer preferentially metastasizes to the omentum, a fatty tissue characterized by immune structures called milky spots, but the cellular dynamics that direct this tropism are unknown. Here, we identified that neutrophil influx into the omentum is a prerequisite premetastatic step in orthotopic ovarian cancer models. Ovarian tumor–derived inflammatory factors stimulated neutrophils to mobilize and extrude chromatin webs called neutrophil extracellular traps (NETs). NETs were detected in the omentum of ovarian tumor–bearing mice before metastasis and of women with early-stage ovarian cancer. NETs, in turn, bound ovarian cancer cells and promoted metastasis. Omental metastasis was decreased in mice with neutrophil-specific deficiency of peptidylarginine deiminase 4 (PAD4), an enzyme that is essential for NET formation. Blockade of NET formation using a PAD4 pharmacologic inhibitor also decreased omental colonization. Our findings implicate NET formation in rendering the premetastatic omental niche conducive for implantation of ovarian cancer cells and raise the possibility that blockade of NET formation prevents omental metastasis.