Pleiotropic effects of negative energy balance in the postpartum dairy cow on splenic gene expression: repercussions for innate and adaptive immunity

D G Morris,R Fitzpatrick,D A Kenny,B Earley,D C Wathes,M G Diskin,J J Murphy,S M Waters,S D Mccarthy,J Patton,A Brass

doi:10.1152/physiolgenomics.90394.2008

Abstract

Increased energy demands to support lactation, coupled with lowered feed intake capacity results in negative energy balance (NEB) and is typically characterized by extensive mobilization of body energy reserves in the early postpartum dairy cow. The catabolism of stored lipid leads to an increase in the systemic concentrations of nonesterified fatty acids (NEFA) and β-hydroxy butyrate (BHB). Oxidation of NEFA in the liver result in the increased production of reactive oxygen species and the onset of oxidative stress and can lead to disruption of normal metabolism and physiology. The immune system is depressed in the peripartum period and early lactation and dairy cows are therefore more vulnerable to bacterial infections causing mastitis and or endometritis at this time. A bovine Affymetrix oligonucleotide array was used to determine global gene expression in the spleen of dairy cows in the early postpartum period. Spleen tissue was removed post mortem from five severe NEB (SNEB) and five medium NEB (MNEB) cows 15 days postpartum. SNEB increased systemic concentrations of NEFA and BHB, and white blood cell and lymphocyte numbers were decreased in SNEB animals. A total of 545 genes were altered by SNEB. Network analysis using Ingenuity Pathway Analysis revealed that SNEB was associated with NRF2-mediated oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, natural killer cell signaling, p53 signaling, downregulation of IL-15, BCL-2, and IFN-γ; upregulation of BAX and CHOP and increased apoptosis with a potential negative impact on innate and adaptive immunity.

Highlights

SUCCESSFUL GENETIC SELECTION programs over the past 30 – 40 yr together with improved nutrition has resulted in the modern dairy cow, which is biologically efficient at producing large volumes of milk exceeding 8,500 l per 305-day lactation
Nonesterified fatty acids (NEFAs) and ketone bodies including ␤-hydroxy butyrate (BHB) are produced by the liver as the fatty acids are metabolized and their systemic concentrations increase in proportion to the degree of fat mobilization
Oxidation of NEFAs in the liver result in the increased production of reactive oxygen species (ROS), decreased paraoxonase activity, and the onset of oxidative stress [77]. This may be linked to depression of the immune system in early lactation [38, 39, 54, 80], resulting in dairy cows becoming more vulnerable to bacterial infections at this time

Summary

Introduction

SUCCESSFUL GENETIC SELECTION programs over the past 30 – 40 yr together with improved nutrition has resulted in the modern dairy cow, which is biologically efficient at producing large volumes of milk exceeding 8,500 l per 305-day lactation. Increased milk production causes severe metabolic demands for increased energy resulting in extensive mobilization of body fat reserves in early lactation This period of negative energy balance (NEB) can persist for many weeks, and fatty acid catabolism can result in the accumulation of triglycerides in the liver and increased systemic concentrations of lipid metabolites in the blood resulting in a period of oxidative stress. This early postpartum period is associated with a dramatic increase in the rate of liver blood flow and metabolism that can compromise liver function and result in production diseases such as ketosis and fatty liver [30, 73]. Cows with fatty liver have higher blood concentrations of the cytokine TNF-␣ before calving and higher concentrations of the acute phase protein serum amyloid A and haptoglobin [1] after calving

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