Macrophage infiltration in the omental and subcutaneous adipose tissues of dairy cows with displaced abomasum

Abstract

High concentrations of plasma nonesterified fatty acids (NEFA), a direct measure of lipolysis, are considered a risk factor for displaced abomasum (DA) and other clinical diseases. In nonruminants, uncontrolled lipolysis is commonly associated with adipose tissue macrophage (ATM) infiltration. In dairy cows, recent studies report ATM infiltration in specific adipose depots during the first week of lactation. Depending on their phenotype, ATM can be broadly classified as classically activated (M1) or alternatively activated (M2). The M1 ATM are considered pro-inflammatory, whereas M2 ATM enhance inflammation resolution. Currently, it is not known whether multiparous transition cows with DA have increased ATM infiltration, and the predominant phenotype of these mononuclear cells remains unclear. The objective of this study was to characterize ATM infiltration into different adipose tissue depots in transition cows with DA (days in milk=7.8±4.6 d; body condition score=2.95±0.10; n=6). Serum samples and biopsies from omental (OM) and subcutaneous (SC) fat depots were obtained during corrective surgery for DA. In an effort to compare ATM infiltration in DA cows with that of healthy cows in anabolic state (AS), adipose biopsies and blood samples were collected from nonlactating, nongestating dairy cows at the time of slaughter (body condition score=3.75±0.12; n=6). Adipose tissues were digested and cells from the stromal vascular fraction (SVF) were analyzed using flow cytometry to establish cell surface expression of specific macrophage markers including CD14, CD11c, CD163, and CD172a. Tissue sections were analyzed by immunohistochemistry to assess ATM localization. Cows with DA were ketotic and had plasma NEFA above 1.0 mEq/L. The same group of cows had significant infiltration of ATM in OM characterized by increased numbers of SVF cells expressing CD14 and CD172a. At the same time, expression of CD11c, and CD163 was significantly higher in SVF from OM and SC of DA cows compared with those from AS animals. Expression of M1 macrophage inflammatory phenotype-related genes CCL2, IL6, and TNFα in SVF from cows with DA was significantly higher than that in healthy cows (AS). Significant populations of ATM in OM and SC depots of cows with DA were localized in multiple cellular aggregates that included multinucleated cells. In contrast, ATM in AS cows were fewer and randomly localized in both SC and OM. Together, these results indicate that infiltration of classically activated ATM is a concurrent finding in DA cases and may be associated with metabolic stress around parturition contributing to the pro-inflammatory status of transition dairy cows. Future studies are needed to establish whether ATM infiltration is more pronounced in cows with DA compared with healthy dairy cows at the same lactation stage and if this increased mononuclear immune cell trafficking has any pathophysiological significance.

Temporal changes in sphingolipids and systemic insulin sensitivity during the transition from gestation to lactation

“…Although prepartum adiposity did not influence total sphingomyelin concentration, we did detect a significant decrease in C18:1 and C20:1-sphingomyelin levels in overweight cows (Fig 7; P < 0.05). Increased adiposity is associated with adipose tissue macrophage infiltration and tumor necrosis factor-α release [64, 65]; therefore, our data supports the possibility that increased adiposity may have predisposed cows to greater inflammation and sphingomyelinase activation. Consistent with sphingomyelin hydrolysis as a source of ceramides, inverse associations between ceramides and sphingomyelins were detected in plasma during prepartum (e.g.…”

Adipose tissue lipolysis and remodeling during the transition period of dairy cows

“…Cells of the innate and adaptive immune systems, such as macrophages, mast cells, lymphocytes, neutrophils, eosinophils, dendritic cells, and NK, exhibit active AT trafficking during health and disease in rodents and humans [80], as well as in dairy cows during the transition period and late lactation [81, 82]…”

“…In dairy cows, ATM infiltration occurs as a response to intense lipolysis. In cases of displaced abomasum in transition dairy cows, macrophages exhibiting a M1 phenotype accumulate in aggregates within omental and subcutaneous depots [81]. During induced NEB in late-lactation cows, lipolysis induced ATM infiltration into subcutaneous and visceral AT, yet no phenotypic change was observed [82].…”

“…In human and mouse studies, the alternative macrophage phenotype has been induced by omega-3 FA molecules and pharmacological agents through peroxisome proliferator-activated receptors [92–94]. Given the intense ATM polarization to M1 during excessive lipolysis in the transition period, the possibility of modulating ATM phenotype in transition dairy cows may offer therapeutic alternatives [81]. …”

“…T-cells were reported to comprise 3–5% of the SVF cells in cows, with or without displaced abomasum, during the transition period and in late lactation [81, 82, 95]. Around 4–7% of SVF cells are B lymphocytes and their numbers are higher in visceral AT than other AT.…”