The Role of Macrophages in Response to Cytokine Signalling

Cells can communicate with each other via signalling molecules in the form of
proteins (typically between 10-15 amino acid residues) called cytokines. Cytokines bind
to specific receptors on their target cells and often mediate cellular changes by
modulating gene expression. Macrophages release many cytokines that coordinate the
immune response against infections and the activity of macrophages is also controlled by
cytokine signalling from other cells. Our understanding of how macrophages respond to
cytokines and the role of the cytokines released by macrophages in immune defence has
helped us devise treatments in the clinics. For example, Calandra T. investigated the link
between macrophage migration inhibitory factor (MIF) and septic shock in experiments
involving antibodies and knockout mice; his work revealed how MIF can be targeted in
clinical interventions to treat septic shock.

Macrophages are an important part of the body’s innate immune defence against
infections. First, macrophages are attracted to sites of tissue damage by β-chemokines
(chemotactic cytokines) produced by endothelial cells and resident macrophages.
Macrophages detect the concentration gradient of chemokines and undergo
rearrangement of the cytoskeleton to migrate by chemotaxis. Chemokines also increase
extravasation of circulating macrophages (monocytes) at sites of tissue damage by
activating integrins called LFA-1 thus facilitating their interaction with intercellular
adhesion molecule 1 (ICAM-1) on endothelial cells. Examples of β-chemokines acting on
macrophages are RANTES (regulated upon activation, normal T cell expressed and
secreted) and MCP-1 (monocyte chemoattractant protein-1).
Macrophages become activated on encountering endotoxins, such as bacterial
lipopolysaccharide (LPS) and unmethylated bacterial DNA, which interact with their
surface Toll-like receptors-4 (TLR4). Helper T cells are also important in macrophage
activation as they release a cytokine called interferon-γ (IFN-γ). Macrophages respond to
IFN-γ by stimulating MHC (major histocompatibility complex) class II protein synthesis
and increasing ‘respiratory burst’ to raise production of microbicidal free radicals.

Once activated, macrophages themselves release cytokines such as tumour

necrosis factor α (TNF-α) to coordinate immune response against infections. As well as
inducing inflammation, TNF-α mediates several important effects: it increases adhesion
molecule synthesis by endothelial cells; it stimulates ‘respiratory burst’ within
neutrophils; it increases production of lymphokines by helper T cells; and it stimulates B
lymphocyte growth. Interleukin-1 (IL-1) and IL-6 are released to promote inflammation
at the site of tissue damage. Activated macrophages release IL-12 to induce IFN-γ
production by helper T cells which activates even more macrophages. MCP-1 is released
to recruit even more monocytes to the site of tissue damage. Polymorphonuclear
leukocytes (PMN) are also recruited due to the release of a chemokine IL-8. The extent of
inflammation at the site of tissue damage is limited by the release of IL-10 and
transforming growth factor-β (TNF-β) which have anti-inflammatory and
immunomodulatory effects. Both INF-α and INF-β are released by macrophages and they
have antiviral and immunomodulatory effects. Activated macrophages also secrete
granulocyte macrophage colony stimulating factor (GM-CSF) which stimulates the
growth of stem cells and their differentiation into granulocytes and macrophages.

Our understanding of how macrophages are involved in cytokine signalling has

led to advances in clinical treatments. For example, macrophages dramatically increase
its production of macrophage migration inhibitory factor (MIF) on encountering LPS,
bacterial endotoxins and exotoxins. It has been recently discovered that MIF has an
important role in mediating innate immunity by upregulating the expression of Toll-like
receptor 4 (TLR4) thus facilitating the recognition of LPS by macrophages. MIF has
clinical relevance because patients with septic shock often have high levels of MIF.
Experimental studies in mice where MIF activity was inhibited, by either administering
anti-MIF antibodies or by deleting the gene for MIF, resulted in protection against septic
shock normally induced on encountering Gram-negative endotoxins or Gram-positive
exotoxins (see Calandra T. 2003). Further experimental studies should hopefully pave the
way to understanding how MIF can be inhibited clinically to treat septic shock.