Myeloid ZFP36L1 Does Not Regulate Inflammation or Host Defense in Mouse Models of Acute Bacterial Infection

Abstract

Zinc finger protein 36, C3H type-like 1 (ZFP36L1) is one of several Zinc Finger Protein 36 (Zfp36) family members, which bind AU rich elements within 3′ untranslated regions (UTRs) to negatively regulate the post-transcriptional expression of targeted mRNAs. The prototypical member of the family, Tristetraprolin (TTP or ZFP36), has been well-studied in the context of inflammation and plays an important role in repressing pro-inflammatory transcripts such as TNF-α. Much less is known about the other family members, and none have been studied in the context of infection. Using macrophage cell lines and primary alveolar macrophages we demonstrated that, like ZFP36, ZFP36L1 is prominently induced by infection. To test our hypothesis that macrophage production of ZFP36L1 is necessary for regulation of the inflammatory response of the lung during pneumonia, we generated mice with a myeloid-specific deficiency of ZFP36L1. Surprisingly, we found that myeloid deficiency of ZFP36L1 did not result in alteration of lung cytokine production after infection, altered clearance of bacteria, or increased inflammatory lung injury. Although alveolar macrophages are critical components of the innate defense against respiratory pathogens, we concluded that myeloid ZFP36L1 is not essential for appropriate responses to bacteria in the lungs. Based on studies conducted with myeloid-deficient ZFP36 mice, our data indicate that, of the Zfp36 family, ZFP36 is the predominant negative regulator of cytokine expression in macrophages. In conclusion, these results imply that myeloid ZFP36 may fully compensate for loss of ZFP36L1 or that Zfp36l1-dependent mRNA expression does not play an integral role in the host defense against bacterial pneumonia.

Expression of Piwi protein MIWI2 defines a distinct population of multiciliated cells

“…Experimental infections. Experimental pneumonias were generated via the intratracheal route as previously described (38). Mice were anesthetized by an i.p.…”

The RNA uridyltransferase Zcchc6 is expressed in macrophages and impacts innate immune responses

“…For primary human macrophages, bronchoalveolar lavage (BAL) was performed on healthy, non-smoking volunteers in accordance with an informed consent protocol approved by Institutional Review Board of Boston University Medical Center as previously conducted [ 26 ]. Alveolar macrophages were isolated by adherence to plastic.…”

RNA Recognition and Immunity—Innate Immune Sensing and Its Posttranscriptional Regulation Mechanisms

“…It is still unclear what roles ZFP36L1 and ZFP36L2 play in myeloid cells. Mice specifically lacking ZFP36L1 in myeloid cells do not show differential responses to acute bacterial pneumonia, although ZFP family genes might function redundantly [128]. Nevertheless, ZFP36L1 regulates senescence-associated secretory phenotype (SASP) by destabilizing Il1b, Il8, and Cdkn1a [129].…”