STAT3 signaling in immunity

Abstract

The transcriptional regulator STAT3 has key roles in vertebrate development and mature tissue function including control of inflammation and immunity. Mutations in human STAT3 associate with diseases such as immunodeficiency, autoimmunity and cancer. Strikingly, however, either hyperactivation or inactivation of STAT3 results in human disease, indicating tightly regulated STAT3 function is central to health. Here, we attempt to summarize information on the numerous and distinct biological actions of STAT3, and highlight recent discoveries, with a specific focus on STAT3 function in the immune and hematopoietic systems. Our goal is to spur investigation on mechanisms by which aberrant STAT3 function drives human disease and novel approaches that might be used to modulate disease outcome.

Keywords: Cytokines; Immune system; Inflammation; STAT3.

Figure 1. STAT3-immune publication numbers

The number of publications listed in PubMed with the query “STAT3 immune” is shown for each year between 1994 and 2015.

Figure 2. Schematic illustration of a STAT3 dimer bound to DNA

A representation of the major STAT3 domains resolved in the X-ray crystal structure of the STAT3-DNA binding complex is shown. Examples of STAT3 mutations associated with STAT3 AD-HIES (LOF) or autoimmunity (GOF) are indicated.

Figure 3. Regulation and effects of STAT3 signaling in myelopoiesis

Activation of STAT3 by the G-CSFR during emergency granulopoiesis drives expression of C/EBPβ and c-Myc in granulocytic progenitors, inducing their proliferation and increasing neutrophil production. IFN-γ stimulates SOCS3 expression, which blocks G-CSFR-STAT3 signaling, and promotes PU.1 and IRF8 induction to drive monocyte generation.

Figure 4. Mechanism of the STAT3 anti-inflammatory response

Activation of STAT3 by IL-6R or IL-10R (not shown) inhibits expression of Ube2n/Ubc13, thereby restraining TLR4 signal transduction via NF-κB and MAP kinase (not shown) cascades.

Figure 5. STAT3 roles in adaptive immunity

Key functions for STAT3 in precursor B cell generation from CLPs, production of IgG-secreting B cells, and generation of Th17, Tfh and CD8⁺ memory T cells are indicated by orange arrows. Also shown, STAT3 inhibitory activity on Treg generation (blunt-ended orange line). Non-STAT3 functions are indicated by thin black lines.