Circulating monocytes in acute pancreatitis

Abstract

Acute pancreatitis is a common gastrointestinal disease characterized by inflammation of the exocrine pancreas and manifesting itself through acute onset of abdominal pain. It is frequently associated with organ failure, pancreatic necrosis, and death. Mounting evidence describes monocytes - phagocytic, antigen presenting, and regulatory cells of the innate immune system - as key contributors and regulators of the inflammatory response and subsequent organ failure in acute pancreatitis. This review highlights the recent advances of dynamic change of numbers, phenotypes, and functions of circulating monocytes as well as their underling regulatory mechanisms with a special focus on the role of lipid modulation during acute pancreatitis.

Keywords: acute pancreatitis; animal models; hypertriglyceridemia; immunity; inflammation; lipotoxicity; monocytes; obesity.

Figure 1

Monocytes in acute pancreatitis. Monocytes are continuously produced in bone marrow (BM) and spleen from hematopoietic stem cells (HSCs) via granulocyte and macrophage progenitors (GMPs), monocyte/dendritic cell (DC) progenitors (MDPs), and common monocyte progenitors (cMoPs) intermediates. During acute and severe inflammation, monocytes might be directly generated from GMPs in response to the need for rapid generation. Non-classical monocytes (NCMs) are derived from classical monocytes (CMs) and might be directly developed from cMoPs. The existence of NCMs in BM/spleen and the regulatory mechanisms of their egress into circulation are disputable and obscure. Intermediate monocytes (IMs) are the transitional cells of CMs and NCMs with distinct functions. The role of NCMs and IMs in acute pancreatitis (AP) is still vague. During AP, pancreatic acinar and ductal cells are injured and liberate damage-associated molecular patterns, cytokines, chemokines, and various pro-inflammatory mediators, leading to the recruitment of circulating monocytes to the inflamed pancreas. Monocytes migration across the endothelium requires a series of sequential adhesive interactions between monocytes and endothelial cells mediated by the indicated endothelial adhesion molecules and monocyte selectin and integrin ligands. When monocytes influx into the pancreas, they either develop into monocyte-derived macrophages/DCs or maintain monocyte-state. The infiltrated monocytes and monocyte-derived macrophages exhibit heterogeneous phenotypes such as pro-inflammatory or anti-inflammatory activities, depending on the environmental cues. Abbreviations: PSGL-1, P-selectin glycoprotein ligand 1; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cellular adhesion molecule-1.

Figure 2

The dynamic changes of monocyte numbers, phenotypes, and functions in acute pancreatitis. Numbers: The number of monocytes in circulation and pancreas is dynamically elevated and might return at various timepoints of experimental and clinical acute pancreatitis (AP). The association of the increased number of monocytes with severity of AP has not been fully verified, despite that the increase in monocytes is more pronounced in more severe phenotype in some cases. Lymphocyte-to-monocyte ratio (LMR) is negatively correlated with AP severity and serves as a predictive index for persistent organ failure and mortality. The augmented number of monocytes within a short time is mainly the function of the release from storage pools. The increased proliferation of monocytes and associated progenitors in bone marrow (BM) and spleen may also contribute to the increased circulating monocytes in AP. Phenotypes: Circulating classical monocytes (CM) levels are associated with escalating AP severity. Novel heterogeneous subsets of monocytes in AP have been identified. The role of non-classical monocytes (NCM) and intermediate monocytes (IM) in AP is still not known. Decreased number of IM in AP might associate with increased susceptibility to infections. Increased M1 and M2 monocytes together with higher M1/M2 ratio can be observed in AP, which possibly correlate with disease severity. Functions: Monocyte activation along with disturbed intracellular multiple signaling profiles and elevated activation markers including CD69 and CD25, leads to massive production of nitric oxide (NO) together with induction of phospholipase A2 (PLA2), cyclooxygenase (COX), and lipoxygenase (LOX). Monocytes in AP exhibit increased adhesion molecules including P-selectin glycoprotein ligand 1 (PSGL-1), platelet endothelial cell adhesion molecule-1 (PECAM-1), and intercellular adhesion molecule 1 (ICAM-1), promoting monocyte adhesion to endothelium and migration to the inflamed pancreas. Impaired phagocytosis of monocytes in AP might be a useful predictor for infectious complication. Heme oxygenase-1 (HO-1)/carbon monoxide (CO) and inducible NO synthase (iNOS)/NO are pivotal gaseous signaling pathways in monocytes of AP. HO-1/CO pathway in monocytes exerts anti-inflammatory effect to dampen AP severity. Increased expression of iNOS in monocytes is observed in AP and the generated NO has dual effect on the production of pro-inflammatory mediators depending on concentrations.

Figure 3

Hypothetical diagram of underlying mechanisms of obesity and dyslipidemias in aggravating acute pancreatitis. Dyslipidemias are prevalent in individuals with metabolically unhealthy obesity (MUO) or metabolically unhealthy normal weight (MUNM), but less prominent or even absent in individuals with metabolically healthy obesity (MHO). Hypertriglyceridemia (HTG), a common form of dyslipidemias, is one of leading etiologies of acute pancreatitis (AP) with increasing global incidence. Obesity, particularly MUO, and dyslipidemias, especially HTG, may exacerbate AP severity in several complex multifactorial ways. Excessive free fatty acids (FFAs) are accumulated via elevated lipolysis of visceral adipocyte triglycerides during AP. FFAs possess regulatory effect on monocytes and may promote their M1 polarization which induces increased production of pro-inflammatory mediators, resulting in amplified systemic inflammation. Of note, local and systemic lipotoxicity of FFAs can directly cause tissue damage and multiple organ failure in AP. Besides FFAs, other distinct lipid species may modulate generation and function of monocytes in AP. Furthermore, various adipokines and cytokines with enhanced secretion in MUO and dyslipidemia are involved in boosting systemic inflammatory response that contributes to aggravated severity of AP.